THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Introduction and Other Protein Targets

1The authors state that there are no conflicts of interest to disclose.

2S1 Introduction and Other Protein Targets

3S8 Adiponectin receptors

4S9 Aryl hydrocarbon receptor

5S10 Non‐enzymatic BRD containing proteins

6S11 CD molecules

7S13 Methyllysine reader proteins

8S14 Fatty acid‐binding proteins

9S16 Notch receptors

10S17 Regulators of G protein Signaling (RGS) proteins

11S17 RZ family

12S18 R4 family

13S19 R7 family

14S19 R12 family

15S20 Sigma receptors

16S21 Transthyretin

17S22 Tubulins

18S23 SARS‐CoV‐2

19S23 Structural proteins

20S24 Polyproteins

21S24 Proteases

22S25 Nucleic acid turnover

23S25 Other proteins

24S27 G protein‐coupled receptors

25S31 Orphan and other 7TM receptors

26S32 Class A Orphans

27S41 Class C Orphans

28S41 Opsin receptors

29S42 Taste 1 receptors

30S43 Taste 2 receptors

31S44 Other 7TM proteins

32S45 5‐Hydroxytryptamine receptors

33S48 Acetylcholine receptors (muscarinic)

34S50 Adenosine receptors

35S52 Adhesion Class GPCRs

36S55 Adrenoceptors

37S59 Angiotensin receptors

38S60 Apelin receptor

39S61 Bile acid receptor

40S62 Bombesin receptors

41S63 Bradykinin receptors

42S64 Calcitonin receptors

43S66 Calcium‐sensing receptor

44S67 Cannabinoid receptors

45S68 Chemerin receptors

46S69 Chemokine receptors

47S73 Cholecystokinin receptors

48S74 Class Frizzled GPCRs

49S76 Complement peptide receptors

50S78 Corticotropin‐releasing factor receptors

51S79 Dopamine receptors

52S81 Endothelin receptors

53S82 G protein‐coupled estrogen receptor

54S83 Formylpeptide receptors

55S84 Free fatty acid receptors

56S86 GABAB receptors

57S87 Galanin receptors

58S89 Ghrelin receptor

59S90 Glucagon receptor family

60S91 Glycoprotein hormone receptors

61S92 Gonadotrophin‐releasing hormone receptors

62S93 GPR18, GPR55 and GPR119

63S94 Histamine receptors

64S96 Hydroxycarboxylic acid receptors

65S97 Kisspeptin receptor

66S98 Leukotriene receptors

67S100 Lysophospholipid (LPA) receptors

68S101 Lysophospholipid (S1P) receptors

69S103 Melanin‐concentrating hormone receptors

70S104 Melanocortin receptors

71S105 Melatonin receptors

72S106 Metabotropic glutamate receptors

73S108 Motilin receptor

74S110 Neuromedin U receptors

75S111 Neuropeptide FF/neuropeptide AF receptors

76S112 Neuropeptide S receptor

77S113 Neuropeptide W/neuropeptide B receptors

78S114 Neuropeptide Y receptors

79S116 Neurotensin receptors

80S117 Opioid receptors

81S119 Orexin receptors

82S120 Oxoglutarate receptor

83S120 P2Y receptors

84S123 Parathyroid hormone receptors

85S124 Platelet‐activating factor receptor

86S125 Prokineticin receptors

87S126 Prolactin‐releasing peptide receptor

88S127 Prostanoid receptors

89S129 Proteinase‐activated receptors

90S131 QRFP receptor

91S132 Relaxin family peptide receptors

92S134 Somatostatin receptors

93S135 Succinate receptor

94S136 Tachykinin receptors

95S137 Thyrotropin‐releasing hormone receptors

96S138 Trace amine receptor

97S139 Urotensin receptor

98S140 Vasopressin and oxytocin receptors

99S142 VIP and PACAP receptors

100S157 Ion channels

101S159 Ligand‐gated ion channels

102S160 5‐HT3 receptors

103S162 Acid‐sensing (proton‐gated) ion channels (ASICs)

104S165 Epithelial sodium channel (ENaC)

105S166 GABA A receptors

106S172 Glycine receptors

107S175 Ionotropic glutamate receptors

108S180 IP3 receptors

109S181 Nicotinic acetylcholine receptors

110S185 P2X receptors

111S187 ZAC

112S188 Voltage‐gated ion channels

113S188 CatSper and Two‐Pore channels

114S190 Cyclic nucleotide‐regulated channels

115S192 Potassium channels

116S193 Calcium‐ and sodium‐activated potassium channels

117S195 Inwardly rectifying potassium channels

118S199 Two‐pore domain potassium channels

119S201 Voltage‐gated potassium channels

120S204 Ryanodine receptors

121S205 Transient Receptor Potential channels

122S219 Voltage‐gated calcium channels

123S222 Voltage‐gated proton channel

124S223 Voltage‐gated sodium channels

125S225 Aquaporins

126S227 Chloride channels

127S228 ClC family

128S230 CFTR

129S231 Calcium activated chloride channel

130S232 Maxi chloride channel

131S233 Volume regulated chloride channels

132S234 Connexins and Pannexins

133S236 Piezo channels

134S237 Sodium leak channel, non‐selective

135S238 Orai channels

136S245 Nuclear hormone receptors

137S247 1A. Thyroid hormone receptors

138S248 1B. Retinoic acid receptors

139S249 1C. Peroxisome proliferator‐activated receptors

140S250 1D. Rev‐Erb receptors

141S251 1F. Retinoic acid‐related orphans

142S252 1H. Liver X receptor‐like receptors

143S253 1I. Vitamin D receptor‐like receptors

144S254 2A. Hepatocyte nuclear factor‐4 receptors

145S255 2B. Retinoid X receptors

146S255 2C. Testicular receptors

147S256 2E. Tailless‐like receptors

148S256 2F. COUP‐TF‐like receptors

149S257 3B. Estrogen‐related receptors

150S257 4A. Nerve growth factor IB‐like receptors

151S258 5A. Fushi tarazu F1‐like receptors

152S259 6A. Germ cell nuclear factor receptors

153S259 0B. DAX‐like receptors

154S260 Steroid hormone receptors

155S260 3A. Estrogen receptors

156S261 3C. 3‐Ketosteroid receptors

157S264 Catalytic receptors

158S266 Cytokine receptor family

159S266 IL‐2 receptor family

160S268 IL‐3 receptor family

161S268 IL‐6 receptor family

162S270 IL‐12 receptor family

163S271 Prolactin receptor family

164S272 Interferon receptor family

165S273 IL‐10 receptor family

166S274 Immunoglobulin‐like family of IL‐1 receptors

167S275 IL‐17 receptor family

168S276 GDNF receptor family

169S277 Integrins

170S281 Pattern recognition receptors

171S281 Toll‐like receptor family

172S283 NOD‐like receptor family

173S285 RIG‐I‐like receptor family

174S285 Receptor guanylyl cyclase (RGC) family

175S286 Transmembrane guanylyl cyclases

176S287 Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclase

177S288 Receptor tyrosine kinases (RTKs)

178S289 Type I RTKs: ErbB (epidermal growth factor) receptor family

179S290 Type II RTKs: Insulin receptor family

180S291 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family

181S292 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family

182S293 Type V RTKs: FGF (fibroblast growth factor) receptor family

183S294 Type VI RTKs: PTK7/CCK4

184S294 Type VII RTKs: Neurotrophin receptor/Trk family

185S295 Type VIII RTKs: ROR family

186S296 Type IX RTKs: MuSK

187S296 Type X RTKs: HGF (hepatocyte growth factor) receptor family

188S297 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family

189S297 Type XII RTKs: TIE family of angiopoietin receptors

190S298 Type XIII RTKs: Ephrin receptor family

191S299 Type XIV RTKs: RET

192S299 Type XV RTKs: RYK

193S300 Type XVI RTKs: DDR (collagen receptor) family

194S300 Type XVII RTKs: ROS receptors

195S301 Type XVIII RTKs: LMR family

196S301 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family

197S302 Type XX RTKs: STYK1

198S302 Receptor serine/threonine kinase (RSTK) family

199S303 Type I receptor serine/threonine kinases

200S304 Type II receptor serine/threonine kinases

201S304 Type III receptor serine/threonine kinases

202S305 RSTK functional heteromers

203S306 Receptor tyrosine phosphatase (RTP) family

204S308 Tumour necrosis factor (TNF) receptor family

205S313 Enzymes

206S318 Acetylcholine turnover

207S318 Adenosine turnover

208S321 Amino acid hydroxylases

209S322 L‐Arginine turnover

210S336 2.1.1.‐ Protein arginine N‐methyltransferases

211S322 Arginase

212S323 Arginine:glycine amidinotransferase

213S323 Dimethylarginine dimethylaminohydrolases

214S324 Nitric oxide synthases

215S325 Carbonic anhydrases

216S325 Carboxylases and decarboxylases

217S326 Carboxylases

218S327 Decarboxylases

219S328 Catecholamine turnover

220S330 Ceramide turnover

221S331 Serine palmitoyltransferase

222S331 Ceramide synthase

223S332 Sphingolipid Δ4‐desaturase

224S332 Sphingomyelin synthase

225S333 Sphingomyelin phosphodiesterase

226S333 Neutral sphingomyelinase coupling factors

227S334 Ceramide glucosyltransferase

228S334 Acid ceramidase

229S334 Neutral ceramidases

230S335 Alkaline ceramidases

231S335 Ceramide kinase

232S336 Chromatin modifying enzymes

233S336 2.1.1.‐ Protein arginine N‐methyltransferases

234S337 3.5.1.‐ Histone deacetylases (HDACs)

235S338 Cyclic nucleotide turnover/signalling

236S338 Adenylyl cyclases (ACs)

237S340 Exchange protein activated by cyclic AMP (EPACs)

238S341 Phosphodiesterases, 3’,5’‐cyclic nucleotide (PDEs)

239S344 Cytochrome P450

240S344 CYP1 family

241S345 CYP2 family: drug metabolising subset

242S346 CYP2 family: physiological enzymes subset

243S346 CYP3 family

244S347 CYP4 family

245S348 CYP5, CYP7 and CYP8 families

246S349 CYP11, CYP17, CYP19, CYP20 and CYP21 families

247S350 CYP24, CYP26 and CYP27 families

248S350 CYP39, CYP46 and CYP51 families

249S351 DNA topoisomerases

250S351 E3 ubiquitin ligase components

251S352 Endocannabinoid turnover

252S353 N‐Acylethanolamine turnover

253S354 2‐Acylglycerol ester turnover

254S355 Eicosanoid turnover

255S355 Cyclooxygenase

256S356 Prostaglandin synthases

257S358 Lipoxygenases

258S359 Leukotriene and lipoxin metabolism

259S359 GABA turnover

260S361 Glycerophospholipid turnover

261S361 Phosphoinositide‐specific phospholipase C

262S363 Phospholipase A2

263S364 Phosphatidylcholine‐specific phospholipase D

264S365 Lipid phosphate phosphatases

265S366 Phosphatidylinositol kinases

266S368 Phosphatidylinositol phosphate kinases

267S369 Haem oxygenase

268S370 Hydrogen sulphide synthesis

269S371 Hydrolases

270S373 Inositol phosphate turnover

271S373 Inositol 1,4,5‐trisphosphate 3‐kinases

272S373 Inositol polyphosphate phosphatases

273S374 Inositol monophosphatase

274S374 Kinases (EC 2.7.x.x)

275S375 Rho kinase

276S375 Protein kinase C (PKC) family

277S376 Alpha subfamily

278S376 Delta subfamily

279S377 Eta subfamily

280S377 Iota subfamily

281S378 FRAP subfamily

282S378 Cyclin‐dependent kinase (CDK) family

283S379 CDK4 subfamily

284S379 GSK subfamily

285S380 Polo‐like kinase (PLK) family

286S381 STE7 family

287S382 Abl family

288S382 Ack family

289S383 Janus kinase (JakA) family

290S383 Src family

291S384 Tec family

292S385 RAF family

293S385 Lanosterol biosynthesis pathway

294S388 Nucleoside synthesis and metabolism

295S389 Paraoxonase (PON) family

296S390 Peptidases and proteinases

297S390 Blood coagulation components

298S391 A1: Pepsin

299S391 A22: Presenilin

300S392 C14: Caspase

301S392 M1: Aminopeptidase N

302S393 M2: Angiotensin‐converting enzymes (ACE and ACE2)

303S393 M10: Matrix metallopeptidase

304S394 M12: Astacin/Adamalysin

305S394 M28: Aminopeptidase Y

306S395 M19: Membrane dipeptidase

307S395 S1: Chymotrypsin

308S396 T1: Proteasome

309S397 S8: Subtilisin

310S397 S9: Prolyl oligopeptidase

311S397 Peptidyl‐prolyl cis/trans isomerases

312S399 Poly ADP‐ribose polymerases

313S399 Prolyl hydroxylases

314S400 Sphingosine 1‐phosphate turnover

315S400 Sphingosine kinase

316S402 Sphingosine 1‐phosphate phosphatase

317S402 Sphingosine 1‐phosphate lyase

318S403 Thyroid hormone turnover

319S404 1.14.13.9 Kynurenine 3‐monooxygenase

320S405 2.5.1.58 Protein farnesyltransferase

321S405 3.5.3.15 Peptidyl arginine deiminases (PADI)

322S406 3.6.5.2 Small monomeric GTPases

323S406 RAS subfamily

324S406 RAB subfamily

325S412 Transporters

326S414 ATP‐binding cassette transporter family

327S415 ABCA subfamily

328S416 ABCB subfamily

329S417 ABCC subfamily

330S418 ABCD subfamily of peroxisomal ABC transporters

331S419 ABCG subfamily

332S419 F‐type and V‐type ATPases

333S420 F‐type ATPase

334S420 V‐type ATPase

335S420 P‐type ATPases

336S421 P1B P‐type ATPases: Cu+‐ATPases

337S421 P2A P‐type ATPases: Ca2+‐ATPases

338S422 P2B P‐type ATPases: Ca2+‐ATPases

339S422 Na+/K+‐ATPases

340S422 H+/K+‐ATPases

341S423 P4 P‐type ATPases: Phospholipid‐transporting ATPases

342S423 P5 P‐type ATPases: Mn2+‐ATPases

343S424 SLC superfamily of solute carriers

344S425 SLC1 family of amino acid transporters

345S425 Glutamate transporter subfamily

346S427 Alanine/serine/cysteine transporter subfamily

347S427 SLC2 family of hexose and sugar alcohol transporters

348S428 Class I transporters

349S428 Class II transporters

350S429 Proton‐coupled inositol transporter

351S430 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)

352S430 SLC3 family

353S430 SLC7 family

354S432 SLC4 family of bicarbonate transporters

355S432 Anion exchangers

356S433 Sodium‐dependent HCO3 − transporters

357S433 SLC5 family of sodium‐dependent glucose transporters

358S434 Hexose transporter family

359S435 Choline transporter

360S436 Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate transporters

361S437 Sodium myo‐inositol cotransporter transporters

362S438 SLC6 neurotransmitter transporter family

363S439 Monoamine transporter subfamily

364S439 GABA transporter subfamily

365S440 Glycine transporter subfamily

366S442 Neutral amino acid transporter subfamily

367S443 SLC8 family of sodium/calcium exchangers

368S444 SLC9 family of sodium/hydrogen exchangers

369S444 SLC10 family of sodium‐bile acid co‐transporters

370S445 SLC11 family of proton‐coupled metal ion transporters

371S446 SLC12 family of cation‐coupled chloride transporters

372S448 SLC13 family of sodium‐dependent sulphate/carboxylate transporters

373S449 SLC14 family of facilitative urea transporters

374S450 SLC15 family of peptide transporters

375S453 SLC16 family of monocarboxylate transporters

376S454 SLC17 phosphate and organic anion transporter family

377S454 Type I sodium‐phosphate co‐transporters

378S455 Sialic acid transporter

379S455 Vesicular glutamate transporters (VGLUTs)

380S456 Vesicular nucleotide transporter

381S456 SLC18 family of vesicular amine transporters

382S457 SLC19 family of vitamin transporters

383S458 SLC20 family of sodium‐dependent phosphate transporters

384S459 SLC22 family of organic cation and anion transporters

385S460 Organic cation transporters (OCT)

386S461 Organic zwitterions/cation transporters (OCTN)

387S461 Organic anion transporters (OATs)

388S462 Urate transporter

389S463 Atypical SLC22B subfamily

390S464 SLC23 family of ascorbic acid transporters

391S465 SLC24 family of sodium/potassium/calcium exchangers

392S466 SLC25 family of mitochondrial transporters

393S466 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily

394S467 Mitochondrial amino acid transporter subfamily

395S468 Mitochondrial phosphate transporters

396S468 Mitochondrial nucleotide transporter subfamily

397S469 Mitochondrial uncoupling proteins

398S469 Miscellaneous SLC25 mitochondrial transporters

399S470 SLC26 family of anion exchangers

400S470 Selective sulphate transporters

401S471 Chloride/bicarbonate exchangers

402S471 Anion channels

403S472 Other SLC26 anion exchangers

404S472 SLC27 family of fatty acid transporters

405S473 SLC28 and SLC29 families of nucleoside transporters

406S474 SLC28 family

407S475 SLC29 family

408S476 SLC30 zinc transporter family

409S477 SLC31 family of copper transporters

410S478 SLC32 vesicular inhibitory amino acid transporter

411S479 SLC33 acetylCoA transporter

412S480 SLC34 family of sodium phosphate co‐transporters

413S481 SLC35 family of nucleotide sugar transporters

414S482 SLC36 family of proton‐coupled amino acid transporters

415S483 SLC37 family of phosphosugar/phosphate exchangers

416S484 SLC38 family of sodium‐dependent neutral amino acid transporters

417S484 System A‐like transporters

418S485 System N‐like transporters

419S485 Orphan SLC38 transporters

420S486 SLC39 family of metal ion transporters

421S487 SLC40 iron transporter

422S488 SLC41 family of divalent cation transporters

423S489 SLC42 family of Rhesus glycoprotein ammonium transporters

424S490 SLC43 family of large neutral amino acid transporters

425S491 SLC44 choline transporter‐like family

426S492 SLC45 family of putative sugar transporters

427S493 SLC46 family of folate transporters

428S494 SLC47 family of multidrug and toxin extrusion transporters

429S495 SLC48 heme transporter

430S495 SLC49 family of FLVCR‐related heme transporters

431S496 SLC50 sugar transporter

432S497 SLC51 family of steroid‐derived molecule transporters

433S498 SLC52 family of riboflavin transporters

434S499 SLC53 Phosphate carriers

435S499 SLC54 Mitochondrial pyruvate carriers

436S500 SLC55 Mitochondrial cation/proton exchangers

437S500 SLC56 Sideroflexins

438S501 SLC57 NiPA‐like magnesium transporter family

439S501 SLC58 MagT‐like magnesium transporter family

440S502 SLC59 Sodium‐dependent lysophosphatidylcholine symporter family

441S502 SLC60 Glucose transporters

442S503 SLC61 Molybdate transporter family

443S503 SLC62 Pyrophosphate transporters

444S504 SLC63 Sphingosine phosphate transporters

445S504 SLC64 Golgi Ca2+/H+ exchangers

446S505 SLC65 NPC‐type cholesterol transporters

447S505 SLC66 Lysosomal amino acid transporters

448S506 SLCO family of organic anion transporting polypeptides

449In order to allow clarity and consistency in pharmacology, there is a need for a comprehensive organisation and presentation of the targets of drugs. This is the philosophy of the IUPHAR/BPS Guide to PHARMACOLOGY presented on the online free access database (http://www.guidetopharmacology.org/). This database is supported by the British Pharmacological Society (BPS), the International Union of Basic and Clinical Pharmacology (IUPHAR), the University of Edinburgh and previously the Wellcome Trust. Data included in the Guide to PHARMACOLOGY are derived in large part from interactions with the subcommittees of the Nomenclature amd Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR). A major influence on the development of the database was Tony Harmar (1951‐2014), who worked with a passion to establish the curators as a team of highly informed and informative individuals, with a focus on high‐quality data input, ensuring a suitably validated dataset. The Editors of the Concise Guide have compiled the individual records, in concert with the team of Curators, drawing on the expert knowledge of these latter subcommittees. The tables allow an indication of the status of the nomenclature for the group of targets listed, usually previously published in Pharmacological Reviews. In the absence of an established subcommittee, advice from several prominent, independent experts has generally been obtained to produce an authoritative consensus on nomenclature, which attempts to fit in within the general guidelines from NC‐IUPHAR. This current edition, the Concise Guide to PHARMACOLOGY 2021/22, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2019/20. It contains data drawn from the online database as a rapid overview of the major pharmacological targets. Thus, there are many fewer targets presented in the Concise Guide compared to the online database. The priority for inclusion in the Concise Guide is the presence of quantitative pharmacological data for human proteins. This means that often orphan family members are not presented in the Concise Guide, although structural information is available on the online database. The organisation of the data is tabular(where appropriate) with a standardised format, where possible on a single page, intended to aid understanding of, and comparison within, a particular target group. The Concise Guide is intended as an initial resource, with links to additional reviews and resources for greater depth and information. Pharmacological and structural data focus primarily on human gene products, wherever possible, with links to HGNC gene nomenclature and UniProt IDs. In a few cases, where data from human proteins are limited, data from other species are indicated. Pharmacological tools listed are prioritised on the basis of selectivity and availability. That is, agents(agonists, antagonists, inhibitors, activators, etc.) are included where they are both available (by donation or from commercial sources, now or in the near future) AND the most selective. The Concise Guide is divided into seven sections, which comprise pharmacological targets of similar structure/function. These are G protein‐coupled receptors, ion channels (combining previous records of ligand‐gated, voltage‐gated and other ion channels), catalytic receptors, nuclear hormone receptors, enzymes, transporters and other protein targets. We hope that the Concise Guide will provide for researchers, teachers and students a state‐of‐the art source of accurate, curated information on the background to their work that they will use in the Introductions to their Research Papers or Reviews, or in supporting their teaching and studies. We recommend that any citations to information in the Concise Guide are presented in the following format:

450Alexander SPH et al. (2021). The Concise Guide to PHARMACOLOGY 2021/22: Overview. Br J Pharmacol 178: S1–S26.

451In this overview are listed protein targets of pharmacological interest, which are not G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, transporters or enzymes. For obvious reasons, we have included potential drug targets of the SARS‐CoV‐2 virus, despite the current limited pharmacological data.

452We are extremely grateful to the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology, for financial support of the website and for advice from the NC‐IUPHAR subcommittees. We thank the University of Edinburgh, who host the www.guidetopharmacology.org website. Previously, IUPHAR and the Wellcome Trust (099156/Z/12/Z]) also supported the initiation and expansion of the database. We are also tremendously grateful to the long list of collaborators from NC‐IUPHAR subcommittees and beyond, who have assisted in the construction of the Concise Guide to PHARMACOLOGY 2021/22 and the online database www.GuideToPHARMACOLOGY.org.

453The authors state that there are no conflicts of interest to disclose.

454– Abscisic acid receptor complex

455S8 Adiponectin receptors

456– Anti‐infective targets

457– Antimalarial targets

458– Other anti‐infective targets

459S9 Aryl hydrocarbon receptor

460– B‐cell lymphoma 2(Bcl‐2) protein family

461– Bromodomain‐containing proteins

462S10 Non‐enzymatic BRD containing proteins

463– Butyrophilin and butyrophilin‐like proteins

464S11 CD molecules

465– Chaperone proteins

466– Lipid binding chaperones

467– Chitinase‐like proteins

468– Chromatin‐interacting transcriptional repressors

469S13 Methyllysine reader proteins

470– Circadian clock proteins

471– Claudins

472– Cytolytic pore‐forming proteins

473– EF‐hand domain containing proteins

474S14 Fatty acid‐binding proteins

475– Guanine nucleotide exchange factors (GEFs)

476– Heat shock proteins

477– Hypoxia‐inducible factors

478– Immune checkpoint proteins

479– Immunoglobulin C1‐set domain‐containing proteins

480– Immunoglobulin C2‐set domain‐containing proteins

481– Immunoglobulin like domain containing proteins

482– Immunoglobulins

483– Inhibitors of apoptosis (IAP) protein family

484– Kelch‐like proteins

485– Kinesins

486– Leucine‐rich repeat proteins

487– Lymphocyte antigens

488– Mitochondrial‐associated proteins

489– Myosin binding proteins

490– Neuropilins and Plexins

491– Non‐catalytic pattern recognition receptors

492S16 Notch receptors

493– Nuclear export proteins

494– Pentraxins

495S17 Regulators of G protein Signaling (RGS) proteins

496S17 RZ family

497S18 R4 family

498S19 R7 family

499S19 R12 family

500– Repulsive guidance molecules

501– Reticulons and associated proteins

502– Ribosomal factors

503– Sialic acid binding Ig like lectins

504S20 Sigma receptors

505– Signal regulatory proteins

506– Tetraspanins

507– Transcription factors

508– Transcription factor regulators

509–NF‐κB regulators

510S21 Transthyretin

511S22 Tubulins

512– Tumour‐associated antigens

513– WD repeat‐containing proteins

514– Plasmodium multidrug resistance family

515S23 SARS‐CoV‐2

516S23 Structural proteins

517S24 Polyproteins

518S24 Proteases

519S25 Nucleic acid turnover

520S25 Other proteins

521Adiponectin receptors (provisional nomenclature, ENSFM00500000270960) respond to the 30 kDa complement‐related protein hormone adiponectin (also known as ADIPOQ: adipocyte, C1q and collagen domain‐containing protein; ACRP30, adipose most abundant gene transcript 1; apM‐1; gelatin‐binding protein: Q15848) originally cloned from adipocytes [69]. Although sequence data suggest 7TM domains, immunological evidence indicates that, contrary to typical 7TM topology, the carboxyl terminus is extracellular, while the amino terminus is intracellular [136]. Signalling through these receptors appears to avoid G proteins; modelling based on the crystal structures of the adiponectin receptors suggested ceramidase acivity, which would make these the first in a new family of catalytic receptors [121].

522Fisman EZ et al. (2014) Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol 13: 103 [PMID:24957699]

523Okada‐Iwabu M et al. (2018) Structure and function analysis of adiponectin receptors toward development of novel antidiabetic agents promoting healthy longevity. Endocr J 65: 971‐977 [PMID:30282888]

524Ruan H et al. (2016) Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 8: 101‐9 [PMID:26993044]

525Wang Y et al. (2017) Cardiovascular Adiponectin Resistance: The Critical Role of Adiponectin Receptor Modification. Trends Endocrinol Metab 28: 519‐530 [PMID:28473178]

526Zhao L et al. (2014) Adiponectin and insulin cross talk: the microvascular connection. Trends Cardiovasc Med 24: 319‐24 [PMID:25220977]

527T‐Cadherin ( CDH13, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [47].

528The aryl hydrocarbon receptor, highly expressed in the liver and barrier organs, is resident in the cytoplasm bound to the chaperone heat shock protein hsp90. Upon agonist activation, the ligand:aryl hydrocarbon receptor complex migrates to the nucleus and binds the aryl hydrocarbon receptor nuclear translocator (ARNT, P27540, also known as HIF1β). The complex regulates transcription of selected genes through interaction with xenobiotic response elements (XRE). Among the genes regulated by the AHR/ARNT complex are cytochrome P450s, particularly CYP1A1, and the period circadian protein homolog 1 (PER1, O15534). The aryl hydrocarbon receptor is also capable of non‐genomic signalling.

529Bock KW. (2019) Aryl hydrocarbon receptor (AHR): From selected human target genes and crosstalk with transcription factors to multiple AHR functions. Biochem Pharmacol 168: 65‐70 [PMID:31228464]

530Bock KW. (2020) Aryl hydrocarbon receptor (AHR) functions: Balancing opposing processes including inflammatory reactions. Biochem Pharmacol 178: 114093 [PMID:32535108]

531Esser C et al. (2015) The aryl hydrocarbon receptor in barrier organ physiology, immunology, and toxicology. Pharmacol Rev 67: 259‐79 [PMID:25657351]

532Roman ÁC et al. (2018) The aryl hydrocarbon receptor in the crossroad of signalling networks with therapeutic value. Pharmacol Ther 185: 50‐63 [PMID:29258844]

533Rothhammer V et al. (2019) The aryl hydrocarbon receptor: an environmental sensor integrating immune responses in health and disease. Nat Rev Immunol 19: 184‐197 [PMID:30718831]

534Shi Y et al. (2020) The aryl hydrocarbon receptor: An environmental effector in the pathogenesis of fibrosis. Pharmacol Res 160: 105180 [PMID:32877693]

535Bromodomains bind proteins with acetylated lysine residues, such as histones, to regulate gene transcription. Listed herein are examples of bromodomain‐containing proteins for which sufficient pharmacology exists.

536Fujisawa T et al. (2017) Functions of bromodomain‐containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol 18: 246‐262 [PMID:28053347]

537Myrianthopoulos V et al. (2019) From bench to bedside, via desktop. Recent advances in the application of cutting‐edge in silico tools in the research of drugs targeting bromodomain modules. Biochem Pharmacol 159: 40‐51 [PMID:30414936]

538Nicholas DA et al. (2017) BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cell Mol Life Sci 74: 231‐243 [PMID:27491296]

539Ramadoss M et al. (2018) Targeting the cancer epigenome: synergistic therapy with bromodomain inhibitors. Drug Discov Today 23: 76‐89 [PMID:28943305]

540Spriano F et al. (2020) Targeting BET bromodomain proteins in cancer: The example of lymphomas. Pharmacol Ther 215: 107631 [PMID:32693114]

541Tang P et al. (2021) Targeting Bromodomain and Extraterminal Proteins for Drug Discovery: From Current Progress to Technological Development. J Med Chem 64: 2419‐2435 [PMID:33616410]

542Cluster of differentiation refers to an attempt to catalogue systematically a series of over 300 cell‐surface proteins associated with immunotyping. Many members of the group have identified functions as enzymes (for example, see CD73 ecto‐5’‐nucleotidase) or receptors (for example, see CD41 integrin, alpha 2b subunit). Many CDs are targeted for therapeutic gain using antibodies for the treatment of proliferative disorders. A full listing of all the Clusters of Differentiation proteins is not possible in the Guide to PHARMACOLOGY; listed herein are selected members of the family targeted for therapeutic gain.

543Bewersdorf JP et al. (2021) Immune checkpoint inhibition in myeloid malignancies: Moving beyond the PD‐1/PD‐L1 and CTLA‐4 pathways. Blood Rev 45: 100709 [PMID:32487480]

544Chi Z et al. (2021) Transcriptional and epigenetic regulation of PD‐1 expression. Cell Mol Life Sci 78: 3239‐3246 [PMID:33738533]

545Gabius HJ et al. (2015) The glycobiology of the CD system: a dictionary for translating marker designations into glycan/lectin structure and function. Trends Biochem Sci 40: 360‐76 [PMID:25981696]

546Huang MY et al. (2021) Combination therapy with PD‐1/PD‐L1 blockade in non‐small cell lung cancer: strategies and mechanisms. Pharmacol Ther 219: 107694 [PMID:32980443]

547Vosoughi T et al. (2019) CD markers variations in chronic lymphocytic leukemia: New insights into prognosis. J Cell Physiol 234: 19420‐19439 [PMID:31049958]

548The endogenous ligands for human PD‐1 are programmed cell death 1 ligand 1 (PD‐L1 aka CD274 (CD274, Q9NZQ7)) and programmed cell death 1 ligand 2 (PD‐L2; PDCD1LG2). These ligands are cell surface peptides, normally involved in immune system regulation. Expression of PD‐1 by cancer cells induces immune tolerance and evasion of immune system attack. Anti‐PD‐1 monoclonal antibodies are used to induce immune checkpoint blockade as a therapeutic intervention in cancer, effectively re‐establishing immune vigilance. Pembrolizumab was the first anti‐PD‐1 antibody to be approved by the US FDA.

549Methyllysine reader proteins bind to methylated proteins, such as histones, allowing regulation of gene expression.

550Daskalaki MG et al. (2018) Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses. J Cell Physiol 233: 6495‐6507 [PMID:29574768]

551Furuya K et al. (2019) Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis. J Biochem 165: 297‐299 [PMID:30605533]

552Levy D. (2019) Lysine methylation signaling of non‐histone proteins in the nucleus. Cell Mol Life Sci 76: 2873‐2883 [PMID:31123776]

553Li J et al. (2019) Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol Life Sci 76: 2899‐2916 [PMID:31147750]

554Shafabakhsh R et al. (2019) Role of histone modification and DNA methylation in signaling pathways involved in diabetic retinopathy. J Cell Physiol 234: 7839‐7846 [PMID:30515789]

555Fatty acid‐binding proteins are low molecular weight (100‐130 aa) chaperones for long chain fatty acids, fatty acyl CoA esters, eicosanoids, retinols, retinoic acids and related metabolites and are usually regarded as being responsible for allowing the otherwise hydrophobic ligands to be mobile in aqueous media. These binding proteins may perform functions extracellularly (e.g. in plasma) or transport these agents; to the nucleus to interact with nuclear receptors (principally PPARs and retinoic acid receptors [99]) or for interaction with metabolic enzymes. Although sequence homology is limited, crystallographic studies suggest conserved 3D structures across the group of binding proteins.

556Gajda AM et al. (2015) Enterocyte fatty acid‐binding proteins (FABPs): different functions of liver and intestinal FABPs in the intestine. Prostaglandins Leukot Essent Fatty Acids 93: 9‐16 [PMID:25458898]

557Glatz JF. (2015) Lipids and lipid binding proteins: a perfect match. Prostaglandins Leukot Essent Fatty Acids 93: 45‐9 [PMID:25154384]

558Hotamisligil GS et al. (2015) Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol 11: 592‐605 [PMID:26260145]

559Matsumata M et al. (2016) Fatty acid binding proteins and the nervous system: Their impact on mental conditions. Neurosci Res 102: 47‐55 [PMID:25205626]

560Nguyen HC et al. (2020) Role of the Fatty Acid Binding Proteins in Cardiovascular Diseases: A Systematic Review. J Clin Med 9: [PMID:33105856]

561Osumi T et al. (2016) Heart lipid droplets and lipid droplet‐binding proteins: Biochemistry, physiology, and pathology. Exp Cell Res 340: 198‐204 [PMID:26524506]

562Although not tested at all FABPs, BMS309403 exhibits high affinity for FABP4 (pIC50 ˜8.8) compared to FABP3 or FABP5 (pIC50<6.6) [27, 118]. HTS01037 is reported to interfere with FABP4 action [42]. Ibuprofen displays some selectivity for FABP4 (pIC50 5.5) relative to FABP3 (pIC50 3.5) and FABP5 (pIC50 3.8) [68]. Fenofibric acid displays some selectivity for FABP5 (pIC50 5.5) relative to FABP3 (pIC50 4.5) and FABP4 (pIC50 4.6) [68]. Multiple pseudogenes for the FABPs have been identified in the human genome.

563Aberrant Notch signalling is implicated in a number of human cancers [59, 80, 108, 126], and there is intense pharmaceutical activity being directed towards achieving clinically effective Notch pathway inhibition [24, 75].

564Fabbro D et al. (2020) Notch Inhibition in Cancer: Challenges and Opportunities. Chimia (Aarau) 74: 779‐783 [PMID:33115560]

565Moore G et al. (2020) Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives. Cells 9: [PMID:32575680]

566Palmer WH et al. (2015) Ligand‐Independent Mechanisms of Notch Activity. Trends Cell Biol 25: 697‐707 [PMID:26437585]

567Previs RA et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res 21: 955‐61 [PMID:25388163]

568Takebe N et al. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12: 445‐64 [PMID:25850553]

569Regulator of G protein Signaling, or RGS, proteins serve an important regulatory role in signaling mediated by G protein‐coupled receptors (GPCRs). They all share a common RGS domain that directly interacts with active, GTP‐bound Gα subunits of heterotrimeric G proteins. RGS proteins stabilize the transition state for GTP hydrolysis on Gα and thus induce a conformational change in the Gα subunit that accelerates GTP hydrolysis, thereby effectively turning off signaling cascades mediated by GPCRs. This GTPase accelerating protein (GAP) activity is the canonical mechanism of action for RGS proteins, although many also possess additional functions and domains. RGS proteins are divided into four families, R4, R7, R12 and RZ based on sequence homology, domain structure as well as specificity towards Gα subunits. For reviews on RGS proteins and their potential as therapeutic targets, see e.g. [5, 45, 79, 93, 105, 106, 107, 138, 140].

570Alqinyah M et al. (2018) Regulating the regulators: Epigenetic, transcriptional, and post‐translational regulation of RGS proteins. Cell Signal 42: 77‐87 [PMID:29042285]

571Fuentes N et al. (2021) RGS proteins, GRKs, and beta‐arrestins modulate G protein‐mediated signaling pathways in asthma. Pharmacol Ther 223: 107818 [PMID:33600853]

572Neubig RR et al. (2002) Regulators of G‐protein signalling as new central nervous system drug targets. Nat Rev Drug Discov 1: 187‐97 [PMID:12120503]

573Sethakorn N et al. (2010) Non‐canonical functions of RGS proteins. Cell Signal 22: 1274‐81 [PMID:20363320]

574Sjögren B. (2017) The evolution of regulators of G protein signalling proteins as drug targets ‐ 20 years in the making: IUPHAR Review 21. Br J Pharmacol 174: 427‐437 [PMID:28098342]

575Sjögren B et al. (2010) Thinking outside of the "RGS box": new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol 78: 550‐7 [PMID:20664002]

576The RZ family of RGS proteins is less well characterized than the other families. It consists of, RGS17(also known as RGSZ2), RGS19 (also known as GAIP) and RGS20 (with several splice variants including RGSZ1 and Ret‐RGS). All members contain an N‐terminal cysteine string motif [62] which is a site of palmitoylation and could serve functions in membrane targeting, protein stability or aid protein‐protein interactions [2, 62]. However, the function in the case of RZ family RGS proteins is not yet fully understood. Members of the RZ family of RGS proteins are the only RGS proteins that have selective GAP activity for Gαz, a function that resulted in the name of the family [31, 71, 127, 134]. However, the members of the RZ family are able to also GAP Gαi/o members with varying selectivity.

577The R4 family of RGS proteins is the largest family of RGS proteins with 10 members. Each of the R4 family members contain only small N‐ and C‐termini apart from the RGS domain. The N‐terminal amphipathic helix present in most R4 family members serves an important function in membrane association and can directly bind phospholipids. In contrast to the RGS domain, which is well conserved among members of the R4 family of RGS proteins, the N‐ and C‐termini vary, enabling specificity of non‐GAP functions. Despite the non‐complex structure of these proteins, several R4 family RGS proteins have been shown to possess additional functions apart from acting as GAPs at activated Gα subunits [11, 96].

578Xie Z et al. (2016) R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity. AAPS J 18: 294‐304 [PMID:26597290]

579The members of the R7 family of RGS proteins [6] are more complex structures than the R4 family and are closely related to the C. elegans homologues EGL‐10 and EAT‐16 that were identified in the early stage of RGS protein research [36, 55]. Apart from the RGS domain, several additional domains are present in these proteins that mediate protein‐protein interactions, sub‐cellular localization and protein stability. All R7 family members form obligatory dimers with Gβ5 through the G‐γ like (GGL) domain and the disheveled‐EGL10‐Pleckstrin homology (DEP) domain [109]. The DEP and DEP helical extension domain interact with R7 binding protein (R7BP) or RGS9 anchoring protein (R9AP; in retina) that serves as a plasma membrane anchoring mechanism [41, 51].

580The R12 family consisting of RGS10, 12 and 14. RGS12 and 14 are large proteins with additional domains that can participate in protein‐protein interactions and other functions. In contrast, RGS10 is a small protein consisting of the RGS domain and small N‐ and C‐termini, similar to members of the R4 family. However, the sequence homology the RGS10 RGS domain clearly places it in the R12 family [58]. The Gαi/o‐Loco(GoLoco) motif in RGS12 and 14 has GDI activity (for Guanine nucleotide Dissociation Inhibitor) towards Gαi1, Gαi2 and Gαi3 [53, 105]. Through this activity RGS12 and RGS14 can inhibit G protein signaling both by accelerating GTP hydrolysis and by preventing G protein activation. Splice variants of RGS12 and RGS14 also contain membrane targeting and protein‐protein interaction domains [97, 111, 112].

581Although termed ’receptors’, the evidence for coupling through conventional signalling pathways is lacking. Initially described as a subtype of opioid receptors, there is only a modest pharmacological overlap and no structural convergence with the G protein‐coupled receptors; the crystal structure of the sigma1 receptor [98] suggests a trimeric structure of a single short transmembrane domain traversing the endoplasmic reticulum membrane, with the bulk of the protein facing the cytosol. A wide range of compounds, ranging from psychoactive agents to antihistamines, have been observed to bind to these sites.

582Chu UB et al. (2016) Biochemical Pharmacology of the Sigma‐1 Receptor. Mol Pharmacol 89: 142‐53 [PMID:26560551]

583Herrando‐Grabulosa M et al. (2021) Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis. Br J Pharmacol 178: 1336‐1352 [PMID:32761823]

584Sambo DO et al. (2018) The sigma‐1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction. Pharmacol Ther 186: 152‐167 [PMID:29360540]

585Schmidt HR et al. (2019) The Molecular Function ofσ Receptors: Past, Present, and Future. Trends Pharmacol Sci 40: 636‐654 [PMID:31387763]

586Su TP et al. (2016) The Sigma‐1 Receptor as a Pluripotent Modulator in Living Systems. Trends Pharmacol Sci 37: 262‐278 [PMID:26869505]

587Vavers E et al. (2019) Allosteric Modulators of Sigma‐1 Receptor: A Review. Front Pharmacol 10: 223 [PMID:30941035]

588(‐)‐pentazocine also shows activity at opioid receptors. The sigma2 receptor has recently been reported to be TMEM97 [4], a 4TM protein partner of NPC1, the Niemann‐Pick C1 protein, a 13TM cholesterol‐binding protein.

589Transthyretin (TTR) is a homo‐tetrameric protein which transports thyroxine in the plasma and cerebrospinal fluid and retinol (vitamin A) in the plasma. Many disease causing mutations in the protein have been reported, many of which cause complex dissociation and protein mis‐assembly and deposition of toxic aggregates amyloid fibril formation [84]. These amyloidogenic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [7, 20], familial amyloid cardiomyopathy(FAC) [49], amyloidotic vitreous opacities, carpal tunnel syndrome [76] and others. In old age, non‐mutated TTR can also form pathological amyloid fibrils [131]. Pharmacological intervention to reduce or prevent TTR dissociation is being pursued as a therapeutic strategy. To date one small molecule kinetic stabilising molecule (tafamidis) has been approved for FAP, and is being evaluated in clinical trials for other TTR amyloidoses.

590Adams D et al. (2019) Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol 15: 387‐404 [PMID:31209302]

591Bezerra F et al. (2020) Modulation of the Mechanisms Driving Transthyretin Amyloidosis. Front Mol Neurosci 13: 592644 [PMID:33362465]

592Dohrn MF et al. (2020) Targeting transthyretin ‐ Mechanism‐based treatment approaches and future perspectives in hereditary amyloidosis. J Neurochem [PMID:33155274]

593Galant NJ et al. (2017) Transthyretin amyloidosis: an under‐recognized neuropathy and cardiomyopathy. Clin Sci 131: 395‐409 [PMID:28213611]

594Griffin JM et al. (2019) Transthyretin cardiac amyloidosis: A treatable form of heart failure with a preserved ejection fraction. Trends Cardiovasc Med [PMID:31889610]

595Excess production and accumulation of TTR causes hereditary transthyretin‐mediated amyloidosis. Two novel drugs are now approved to combat this disease: inotersen(Tegsedi ® ) [52] and patisiran(Onpattro ® ) [46]. Both of these drugs act to reduce the amount of TTR protein (both wild type and mutant) produced in the liver, but by slightly different mechanisms. Inotersen is an antisense oligonucleotide inhibitor of TTR synthesis, whereas patisiran is a double‐stranded small interfering RNA (which targets a conserved sequence in the 3’ UTR of mutant and wild‐type TTR mRNA). Inotersen is administered subcutaneously, and patisiran is delivered by intravenous infusion in a lipid nanoparticle formulation.

596Tubulins are a family of intracellular proteins most commonly associated with microtubules, part of the cytoskeleton. They are exploited for therapeutic gain in cancer chemotherapy as targets for agents derived from a variety of natural products: taxanes, colchicine and vinca alkaloids. These are thought to act primarily throughβ‐tubulin, thereby interfering with the normal processes of tubulin polymer formation and disassembly.

597Arnst KE et al. (2019) Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy. Med Res Rev 39: 1398‐1426 [PMID:30746734]

598Boiarska Z et al. (2021) Microtubule‐targeting agents and neurodegeneration. Drug Discov Today 26: 604‐615 [PMID:33279455]

599Eshun‐Wilson L et al. (2019) Effects of α‐tubulin acetylation on microtubule structure and stability. Proc Natl Acad Sci USA 116: 10366‐10371 [PMID:31072936]

600Gadadhar S et al. (2017) The tubulin code at a glance. J Cell Sci 130: 1347‐1353 [PMID:28325758]

601Magiera MM et al. (2018) Tubulin Posttranslational Modifications and Emerging Links to Human Disease. Cell 173: 1323‐1327 [PMID:29856952]

602Penna LS et al. (2017) Anti‐mitotic agents: Are they emerging molecules for cancer treatment? Pharmacol Ther 173: 67‐82 [PMID:28174095]

603Coronaviruses are large, often spherical, enveloped, single‐stranded positive‐sense RNA viruses, ranging in size from 80–220 nm. Their genomes and protein structures are highly conserved. Three coronaviruses have emerged over the last 20 years as serious human pathogens: SARS‐CoV was identified as the causative agent in an outbreak in 2002–2003, Middle East respiratory syndrome (MERS) CoV emerged in 2012 and the novel coronavirus SARS‐CoV‐2 emerged in 2019–2020. SARS‐CoV‐2 is the virus responsible for the infectious disease termed COVID‐19 (WHO Technical Guidance 2020).

604Alexander SPH et al. (2020) A rational roadmap for SARS‐CoV‐2/COVID‐19 pharmacotherapeutic research and development: IUPHAR Review 29. Br J Pharmacol, 177 (21): 4942‐4966. [PMID:32358833]

605Cannalire R et al. (2020) Targeting SARS‐CoV‐2 Proteases and Polymerase for COVID‐19 Treatment: State of the Art and Future Opportunities. J Med Chem, [Epub ahead of print]. [PMID:33186044]

606Cui J et al. (2019) Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol, 17 (3): 181‐192. [PMID:30531947]

607Desforges M et al. (2019) Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses, 12 (1). [PMID:31861926]

608Song Z et al. (2019) From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses, 11 (1). [PMID:30646565]

609Zumla A et al. (2016) Coronaviruses ‐ drug discovery and therapeutic options. Nat Rev Drug Discov, 15(5): 327‐47. [PMID:26868298]

610The virus particle has four structural proteins. The envelope, membrane and spike proteins are on the viral surface, while the polybasic nucleoprotein enables the tight coiling of the viral RNA.

611The viral RNA encodes two overlapping polyproteins which are cleaved autocatalytically by intrinsic proteases (see below).

612The component proteins are non‐structural and are involved in the transcription and replication of viral proteins and RNA.