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No retraction, correction or concern found when last checked on Oct 18, 2026.

Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A

Kris M. White, Romel Rosales, Soner Yildiz and 23 more

Science · 2021 · CC BY

doi:10.1126/science.abf4058

Abstract

Hurting the virus by targeting the host Many host proteins play a role in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and some are required for viral replication and translation. There are efforts toward finding drugs that target viral proteins, but a complementary approach is to target these required host proteins. White et al. explored the antiviral activity of the cyclic depsipeptide drug plitidepsin, which targets the hosts cell's translational machinery (see the Perspective by Wong and Damania). The authors show that in cells, the drug is substantially more potent than remdesivir against SARS-CoV-2, with limited cellular toxicity. Prophylactic treatment protected mice against SARS-CoV-2 infection, so further investigation of plitidepsin as a therapeutic is warranted. Science , this issue p. 926 ; see also p. 884

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

Over the past 20 years, three novel coronaviruses have been introduced into the human population, causing substantial morbidity and mortality. The severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) epidemics were each limited in scope, but both are associated with severe disease and high mortality rates. The ongoing COVID-19 pandemic caused by the SARS-CoV-2 virus is the result of a zoonotic transmission event, similar to previous coronavirus epidemics. Recent studies have detected many SARS-like and MERS-like coronaviruses in natural bat reservoirs and have shown them to be capable of replication in human lung cells in vitro. This suggests the presence of a large reservoir of coronaviruses with pandemic potential. Antiviral therapeutics are urgently needed to combat SARS-CoV-2 in the current pandemic and will be the first line of defense for the future coronavirus epidemics that appear more likely as the human population expands in close contact with animal reservoirs.

COVID-19 is a viral-induced inflammatory disease of the airways and lungs with multi-organ involvement that can cause severe respiratory and systemic issues. SARS-CoV-2 replication in the lungs leads to inflammatory, innate, and adaptive immune responses that cause substantial host tissue damage. COVID-19 can lead to end-stage lung disease and systemic involvement with currently limited treatment options and poor prognoses. The current standards of care include oxygen therapy and ventilation, along with the antiviral remdesivir and the anti-inflammatory dexamethasone. Remdesivir and dexamethasone have each improved patient outcomes in clinical trials and have been approved for emergency use by regulatory agencies, but remdesivir in particular has shown limited efficacy and dexamethasone is a steroid that does not directly inhibit viral replication. This leaves a continued need for the development or repurposing of antiviral drugs for the treatment of COVID-19.

Our previously published SARS-CoV-2 and pan-coronaviral interactomes highlighted 332 host proteins that are likely to play a role in the viral life cycle of SARS-CoV-2. In that work we tested 47 existing drugs that were known to modulate these identified host proteins, with many of these drugs showing substantial antiviral activity against SARS-CoV-2 in cell culture. Of the inhibitors tested, those that targeted the eukaryotic translation machinery (eIF4H interacts with SARS-CoV-2 Nsp9) demonstrated particularly potent antiviral activities. Zotatafin, an inhibitor of eIF4A (a partner of eIF4H), had a 90% inhibitory concentration (IC90) of 154 nM, and ternatin-4, an inhibitor of eEF1A that has potential interactions with multiple coronavirus proteins, had an IC90 of 15 nM against SARS-CoV-2 in Vero E6 cells.

Plitidepsin is a potent inhibitor of SARS-CoV-2 in vitro

In an effort to further explore the therapeutic potential of host eEF1A as a target for the treatment of COVID-19, we evaluated the eEF1A inhibitor plitidepsin (aplidin), which has limited clinical approval for the treatment of multiple myeloma. Plitidepsin has also successfully undergone a phase I/II clinical study for the treatment of COVID-19 by the pharmaceutical company PharmaMar and is moving forward into a phase II/III COVID-19 study. We first tested plitidepsin inhibition of SARS-CoV-2 replication using an immunofluorescence-based antiviral screening assay in Vero E6 cells. Plitidepsin inhibited SARS-CoV-2 with an IC90 of 1.76 nM (Fig. 1B), which was 9 times as potent as ternatin-4 and 87.5 times as potent as zotatafin in the same assay. We next tested plitidepsin in the same antiviral assay using a human cell line (hACE2-293T). The anti–SARS-CoV-2 activity of plitidepsin was even more potent in human cells, with an IC90 of 0.88 nM (Fig. 1D), which is more potent than remdesivir tested in the same cell line by a factor of 27.5 (Fig. 1C). The cytotoxicity of plitidepsin was examined in parallel with antiviral activity; at all concentrations in both cell types, we observed a cytostatic impact on cell proliferation (Fig. 1, B and D). We had previously found the lack of a dose-response curve in our cytotoxic assay to be suggestive of a cytostatic, rather than cytotoxic, effect on cells, but further work is required to confirm this hypothesis. Finally, we tested the antiviral effect of plitidepsin in an established model of human pneumocyte-like cells. We found that treatment with plitidepsin inhibited SARS-CoV-2 replication (Fig. 1E) with an IC90 of 3.14 nM and a selectivity index of 40.4, which suggests that plitidepsin has potent antiviral activity in primary human lung cells.

In an effort to better understand the mechanism of action through which plitidepsin inhibits SARS-CoV-2 infection, we performed a time-of-addition assay in which plitidepsin or remdesivir was added to hACE2-293T cells at –2, 0, +2, or +4 hours relative to infection. In this 8-hour single-cycle infection, we found that 20 nM plitidepsin strongly inhibited nucleocapsid protein expression even when added 4 hours after infection (Fig. 1F). This is indicative of a cytoplasmic replication-stage inhibitor, which is consistent with the predicted antiviral mechanism of a known translation inhibitor.

Remdesivir is part of the current standard of care for the treatment of COVID-19. We therefore assessed the dynamics between the antiviral effects of plitidepsin and remdesivir when used together in vitro. Our analysis using the Synergyfinder software suggests that plitidepsin has an additive effect with remdesivir (fig. S2) and would be a potential candidate to be considered in a combined therapy with the current standard of care.

Plitidepsin antiviral activity against SARS-CoV-2 is mediated through the inhibition of eEF1A

Plitidepsin inhibits the activity of the host factor eEF1A and is predicted to interact with the same binding site as didemnin B, which is structurally related to plitidepsin, and the structurally unrelated ternatin-4. Exogenous overexpression of an Ala399 → Val (A399V) mutant of eEF1A confers resistance in cancer cells to both didemnin B and ternatin-4 inhibition, and we predicted that it may similarly affect plitidepsin. We examined whether this A399V mutation could mitigate the observed anti–SARS-CoV-2 activity of plitidepsin. First, we transiently cotransfected 293T cells with expression plasmids for hACE2 and either wild-type eEF1A (eEF1A-WT) or eEF1A-A399V, which were confirmed to be expressed in ~30% of cells by means of immunofluorescent staining for the Flag epitope (fig. S1). We then measured the antiviral activity of plitidepsin against SARS-CoV-2 in these transfected 293T cells. Transfection with eEF1A-A399V, but not eEF1A-WT, increased the IC90 of plitidepsin by a factor of >10 (Fig. 2A). No impact from the A399V mutant transfection was observed upon plitidepsin inhibition of cell proliferation (Fig. 2D), consistent with observations of ternatin-4. The differential effect of eEF1A-A399V transient transfection between the antiviral and antiproliferative impact of plitidepsin is consistent with previous findings that coronaviruses are considerably more sensitive to translation perturbations than the host cell. We then generated an eEF1A-A399V CRISPR knock-in 293T cell line (293T-A399V) to further evaluate the role of eEF1A inhibition in the antiviral activity of plitidepsin. We found that this 293T-A399V cell line was refractory to the SARS-CoV-2 antiviral activity of plitidepsin by a factor of >12 as compared to the parental cell line (Fig. 2B) but did not have a similar impact on remdesivir inhibition (Fig. 2C). Furthermore, we found that plitidepsin antiviral activity could be almost fully restored through transient transfection of the 293T-A399V cells with wild-type, but not mutant, eEF1A (Fig. 2B). This 293T-A399V cell line was also resistant to the antiproliferative activity of plitidepsin, and this could only be partially rescued by transfection of the wild-type protein (Fig. 2E), again similar to previous results with ternatin-4. Furthermore, small interfering RNA (siRNA) silencing of eEF1A protein expression during SARS-CoV-2 infection led to a large reduction in viral N protein levels but had no impact on the GAPDH control (Fig. 2F). Taken together, this evidence indicates that the antiviral activity of plitidepsin is mediated through eEF1A inhibition and confirms eEF1A as a druggable target for the inhibition of SARS-CoV-2 replication.

We next explored the impact of plitidepsin treatment on viral RNA and protein production over the course of SARS-CoV-2 infection. We analyzed the SARS-CoV-2 genomic and N subgenomic RNA content of Vero E6 cells infected with SARS-CoV-2 at a multiplicity of infection (MOI) of 1 at 4, 8, 12, and 24 hours after infection in the presence or absence of equivalent inhibitory doses of plitidepsin or remdesivir. We found that plitidepsin significantly reduced genomic RNA content at 8 and 12 hours after infection and fell just short of significance at the 24-hour time point, similar to remdesivir treatment (Fig. 3A). Interestingly, plitidepsin had a much greater impact on the accumulation of the N subgenomic RNA. Plitidepsin greatly reduced the subgenomic RNA expression as early as 4 hours after infection and maintained a significant impact throughout the time course (Fig. 3B). Remdesivir had no effect on N subgenomic RNA at 4 hours, but did show a reduction at all other time points tested. We then measured the viral N protein levels in the presence and absence of plitidepsin or remdesivir treatment. Similar to RNA levels, plitidepsin had a more potent and sustained inhibition of the expression the N protein over the time course of infection relative to remdesivir (Fig. 3, C and D). This specific inhibition of N subgenomic RNA expression, particularly early in infection, is likely a result of the inhibition of viral translation by plitidepsin. It was previously shown that coronaviruses are highly sensitive to translation inhibitors and that negative-sense genome accumulation is more greatly affected than the positive sense. The current model of coronavirus discontinuous transcription has been guided by evidence that subgenomic RNA formation occurs during negative strand synthesis. Therefore, a translation inhibitor that has a greater impact on negative-sense RNA production would also be expected to specifically reduce subgenomic RNA formation and accumulation, as we observed with plitidepsin. Furthermore, consistent with an impact of plitidepsin in protein translation, N protein levels were more greatly reduced in plitidepsin-treated cells than in remdesivir-treated cells at 24 hours after infection, when levels of N RNA were equivalent between these two treatments.

Plitidepsin shows in vivo antiviral efficacy in mouse models of SARS-CoV-2 infection

Plitidepsin has been clinically developed for the treatment of multiple myeloma with a well-established safety profile and pharmacokinetics. Initially, plitidepsin underwent a large clinical development program in which cancer patients were treated with plitidepsin as a single agent in several phase I and II clinical trials. Results gathered from these clinical studies demonstrated that the probability of having cardiac adverse events, a concern in COVID-19 patients, was not significantly affected by plitidepsin treatment, although these events were found in other chemically related compounds that display a different mechanism of action. It is worth highlighting that plitidepsin had a good safety profile in a phase I clinical trial, which administered a total of 11.4 mg spaced over 5 days of treatment. The dose level used in the COVID-19 proof-of-concept phase I study had a maximum total of 7.5 mg spaced over 3 days.

On the basis of these clinical safety data and good pharmacokinetics (fig. S3A), we determined that a concentration of plitidepsin an order of magnitude greater than the demonstrated in vitro IC90 could be safely achieved in the lungs of mice using a single daily dose. Therefore, we tested the in vivo efficacy of plitidepsin in two different established animal models of SARS-CoV-2 infection. First, we used a human ACE2-expressing adenovirus to transduce the naturally resistant wild-type BALB/c mice and sensitize them to SARS-CoV-2 infection (Fig. 4A). Five days after adenovirus transduction, mice were infected with 1 × 104 plaque-forming units (pfu) of SARS-CoV-2. As a proof-of-principle experiment, we performed prophylactic dosing with 0.3 mg/kg or 1 mg/kg plitidepsin 2 hours before infection with SARS-CoV-2. The 0.3 mg/kg group received continued dosing once per day for 2 more days, whereas the 1 mg/kg group received only that single dose (Fig. 4B). SARS-CoV-2 lung titers were quantified from two independent experiments for the plitidepsin groups and compared to vehicle and remdesivir controls (Fig. 4C). There was a reduction of nearly 2 log units in SARS-CoV-2 viral titers in the lungs of the 0.3 mg/kg plitidepsin group relative to the vehicle control group, whereas there was a reduction of 1.5 log units observed from the single dose of 1 mg/kg plitidepsin. Note that we used a very high concentration of remdesivir in these assays (50 mg/kg) because of the known high concentration of esterases present in mouse serum that degrade remdesivir.

We then performed a study in the K18-hACE2 mouse model (Fig. 5A), which supports a robust SARS-CoV-2 infection, in which the 0.3 mg/kg dosage of plitidepsin was assessed for ability to reduce viral titers and inflammation in the lung. K18-hACE2 mice were treated with one daily dose of plitidepsin for 3 days starting 2 hours before infection with SARS-CoV-2 (Fig. 5B). We found a reduction of 2 log units in viral lung titers at day 3, similar to two daily 50 mg/kg doses of remdesivir (Fig. 5C). Histopathology analysis (Fig. 5D) also showed a reduction of lung inflammation in plitidepsin-treated mice (histopathology score of 1/16) over vehicle-treated (histopathology score of 5.4/16) and remdesivir-treated (histopathology score of 2.3/16) mice at day 3 after infection (Fig. 5E). There was no peribronchiolar inflammation noted in the plitidepsin-treated group. Taken together, these experiments show that plitidepsin treatment can reduce the replication of SARS-CoV-2 by two orders of magnitude and reduce lung inflammation in vivo, and has compelling potential for clinical efficacy for the treatment of COVID-19.

Discussion

The ongoing SARS-CoV-2 pandemic has created the immediate need for antiviral therapeutics that can be moved into the clinic within months rather than years. This led us to screen clinically approved drugs with established bioavailability, pharmacokinetics, and safety profiles. Our previous study of the SARS-CoV-2 interactome led us to eEF1A as a druggable target with the potential for potent inhibition of SARS-CoV-2 in vitro. eEF1A has been previously described to be an important host factor for the replication of many viral pathogens, including influenza virus and respiratory syncytial virus. Specifically, it has been found to be involved in transmissible gastroenteritis coronavirus replication and was detected in SARS-CoV virions. Therefore, inhibition of eEF1A as a strategy for the treatment of viral infection may extend to other human coronaviruses and beyond to unrelated viral pathogens. This potential for broad-spectrum antiviral activity makes plitidepsin an intriguing candidate for further exploration as a treatment for viral infections with no clinically approved therapeutics. It is also important to note that a host-targeted antiviral such as plitidepsin offers protection from naturally occurring viral mutants, to which viral-targeted therapeutics and vaccines are more susceptible. In fact, plitidepsin was found to maintain nanomolar potency against the B.1.1.7 variant recently discovered in the United Kingdom.

In our animal experiments, we did detect a slight body weight loss of mice that were treated with plitidepsin daily, whereas mice that received a single 1 mg/kg dose did not lose any weight while still exhibiting reductions in viral lung titers (fig. S3B). It is unclear whether this observed toxicity is mouse-specific, and although toxicity is a concern with any host-targeted antiviral, the safety profile of plitidepsin is well established in humans. Furthermore, the dose of plitidepsin being used in an ongoing COVID-19 clinical trial is substantially lower than used in these experiments and it has been well tolerated in patients with minimal side effects. Interestingly, the most well-established and effective steroid for the treatment of COVID-19, dexamethasone, is also a commonly used treatment for multiple myeloma. This has led to plitidepsin already having an established safety profile with concurrent dexamethasone treatment and should allow for clinicians to treat with both drugs if warranted. This study establishes plitidepsin as a host-targeted anti–SARS-CoV-2 agent with in vivo efficacy. Our data and the initial positive results from PharmaMar’s clinical trial suggest that plitidepsin should be strongly considered for expanded clinical trials for the treatment of COVID-19.

References 64

  1. 1.

    World Health Organization, “Middle East respiratory syndrome coronavirus (MERS-CoV)”; www.who.int/emergencies/mers-cov/en/.

    Not in our library

  2. 2.

    E. de Wit, N. van Doremalen, D. Falzarano, V. J. Munster, SARS and MERS: Recent insights into emerging coronaviruses. Nat. Rev. Microbiol. 14, 523–534 (2016 ).

    Not in our library10.1038/nrmicro.2016.81

  3. 3.

    D. Wang, B. Hu, C. Hu, F. Zhu, X. Liu, J. Zhang, B. Wang, H. Xiang, Z. Cheng, Y. Xiong, Y. Zhao, Y. Li, X. Wang, Z. Peng, Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 323, 1061–1069 (2020 ).

    Not in our library10.1001/jama.2020.1585

  4. 4.

    Y. Z. Zhang, E. C. Holmes, A Genomic Perspective on the Origin and Emergence of SARS-CoV-2. Cell 181, 223–227 (2020 ).

    Not in our library10.1016/j.cell.2020.03.035

  5. 5.

    K. G. Andersen, A. Rambaut, W. I. Lipkin, E. C. Holmes, R. F. Garry, The proximal origin of SARS-CoV-2. Nat. Med. 26, 450–452 (2020 ).

    Not in our library10.1038/s41591-020-0820-9

  6. 6.
    Bat origin of human coronaviruses · 2015
    No notice
  7. 7.
    Further Evidence for Bats as the Evolutionary Source of Middle East Respiratory Syndrome Coronavirus · 2017
    No notice
  8. 8.

    V. D. Menachery, B. L. Yount Jr.., A. C. Sims, K. Debbink, S. S. Agnihothram, L. E. Gralinski, R. L. Graham, T. Scobey, J. A. Plante, S. R. Royal, J. Swanstrom, T. P. Sheahan, R. J. Pickles, D. Corti, S. H. Randell, A. Lanzavecchia, W. A. Marasco, R. S. Baric, SARS-like WIV1-CoV poised for human emergence. Proc. Natl. Acad. Sci. U.S.A. 113, 3048–3053 (2016 ).

    Not in our library10.1073/pnas.1517719113

  9. 9.

    V. D. Menachery, B. L. Yount Jr.., K. Debbink, S. Agnihothram, L. E. Gralinski, J. A. Plante, R. L. Graham, T. Scobey, X.-Y. Ge, E. F. Donaldson, S. H. Randell, A. Lanzavecchia, W. A. Marasco, Z.-L. Shi, R. S. Baric, A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat. Med. 21, 1508–1513 (2015 ).

    Not in our library10.1038/nm.3985

  10. 10.

    P. C. Woo, S. K. P. Lau, K. S. M. Li, R. W. S. Poon, B. H. L. Wong, H. W. Tsoi, B. C. K. Yip, Y. Huang, K. H. Chan, K. Y. Yuen, Molecular diversity of coronaviruses in bats. Virology 351, 180–187 (2006 ).

    Not in our library10.1016/j.virol.2006.02.041

  11. 11.
    Highlight of Immune Pathogenic Response and Hematopathologic Effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 Infection · 2020
    No notice
  12. 12.

    C. D. Spinner, R. L. Gottlieb, G. J. Criner, J. R. Arribas López, A. M. Cattelan, A. Soriano Viladomiu, O. Ogbuagu, P. Malhotra, K. M. Mullane, A. Castagna, L. Y. A. Chai, M. Roestenberg, O. T. Y. Tsang, E. Bernasconi, P. Le Turnier, S.-C. Chang, D. SenGupta, R. H. Hyland, A. O. Osinusi, H. Cao, C. Blair, H. Wang, A. Gaggar, D. M. Brainard, M. J. McPhail, S. Bhagani, M. Y. Ahn, A. J. Sanyal, G. Huhn, F. M. Marty, Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA 324, 1048–1057 (2020 ).

    Not in our library10.1001/jama.2020.16349

  13. 13.

    Y. Wang, D. Zhang, G. Du, R. Du, J. Zhao, Y. Jin, S. Fu, L. Gao, Z. Cheng, Q. Lu, Y. Hu, G. Luo, K. Wang, Y. Lu, H. Li, S. Wang, S. Ruan, C. Yang, C. Mei, Y. Wang, D. Ding, F. Wu, X. Tang, X. Ye, Y. Ye, B. Liu, J. Yang, W. Yin, A. Wang, G. Fan, F. Zhou, Z. Liu, X. Gu, J. Xu, L. Shang, Y. Zhang, L. Cao, T. Guo, Y. Wan, H. Qin, Y. Jiang, T. Jaki, F. G. Hayden, P. W. Horby, B. Cao, C. Wang, Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 395, 1569–1578 (2020 ).

    Not in our library10.1016/s0140-6736(20)31022-9

  14. 14.

    RECOVERY Collaborative Group, Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report. N. Engl. J. Med. NEJMoa2021436 (2020 ).

    Not in our library10.1016/j.peptides.2009.02.008

  15. 15.

    WHO Solidarity Trial Consortium, Repurposed Antiviral Drugs for COVID-19—Interim WHO SOLIDARITY Trial Results. N. Engl. J. Med. NEJMoa2023184 (2020 ).

    Not in our library10.1016/j.peptides.2009.02.008

  16. 16.

    D. E. Gordon, G. M. Jang, M. Bouhaddou, J. Xu, K. Obernier, K. M. White, M. J. O’Meara, V. V. Rezelj, J. Z. Guo, D. L. Swaney, T. A. Tummino, R. Hüttenhain, R. M. Kaake, A. L. Richards, B. Tutuncuoglu, H. Foussard, J. Batra, K. Haas, M. Modak, M. Kim, P. Haas, B. J. Polacco, H. Braberg, J. M. Fabius, M. Eckhardt, M. Soucheray, M. J. Bennett, M. Cakir, M. J. McGregor, Q. Li, B. Meyer, F. Roesch, T. Vallet, A. Mac Kain, L. Miorin, E. Moreno, Z. Z. C. Naing, Y. Zhou, S. Peng, Y. Shi, Z. Zhang, W. Shen, I. T. Kirby, J. E. Melnyk, J. S. Chorba, K. Lou, S. A. Dai, I. Barrio-Hernandez, D. Memon, C. Hernandez-Armenta, J. Lyu, C. J. P. Mathy, T. Perica, K. B. Pilla, S. J. Ganesan, D. J. Saltzberg, R. Rakesh, X. Liu, S. B. Rosenthal, L. Calviello, S. Venkataramanan, J. Liboy-Lugo, Y. Lin, X.-P. Huang, Y. Liu, S. A. Wankowicz, M. Bohn, M. Safari, F. S. Ugur, C. Koh, N. S. Savar, Q. D. Tran, D. Shengjuler, S. J. Fletcher, M. C. O’Neal, Y. Cai, J. C. J. Chang, D. J. Broadhurst, S. Klippsten, P. P. Sharp, N. A. Wenzell, D. Kuzuoglu-Ozturk, H.-Y. Wang, R. Trenker, J. M. Young, D. A. Cavero, J. Hiatt, T. L. Roth, U. Rathore, A. Subramanian, J. Noack, M. Hubert, R. M. Stroud, A. D. Frankel, O. S. Rosenberg, K. A. Verba, D. A. Agard, M. Ott, M. Emerman, N. Jura, M. von Zastrow, E. Verdin, A. Ashworth, O. Schwartz, C. d’Enfert, S. Mukherjee, M. Jacobson, H. S. Malik, D. G. Fujimori, T. Ideker, C. S. Craik, S. N. Floor, J. S. Fraser, J. D. Gross, A. Sali, B. L. Roth, D. Ruggero, J. Taunton, T. Kortemme, P. Beltrao, M. Vignuzzi, A. García-Sastre, K. M. Shokat, B. K. Shoichet, N. J. Krogan, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020 ).

    Not in our library10.1038/s41586-020-2286-9

  17. 17.
    Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms · 2020
    No notice
  18. 18.

    J. T. Ernst, P. A. Thompson, C. Nilewski, P. A. Sprengeler, S. Sperry, G. Packard, T. Michels, A. Xiang, C. Tran, C. J. Wegerski, B. Eam, N. P. Young, S. Fish, J. Chen, H. Howard, J. Staunton, J. Molter, J. Clarine, A. Nevarez, G. G. Chiang, J. R. Appleman, K. R. Webster, S. H. Reich, Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase. J. Med. Chem. 63, 5879–5955 (2020 ).

    Not in our library10.1021/acs.jmedchem.0c00182

  19. 19.

    M. Ito, J. Ito, H. Kitazawa, K. Shimamura, T. Fukami, S. Tokita, K. Shimokawa, K. Yamada, A. Kanatani, D. Uemura, (–)-Ternatin inhibits adipogenesis and lipid metabolism in 3T3-L1 cells. Peptides 30, 1074–1081 (2009 ).

    Not in our library10.1016/j.peptides.2009.02.008

  20. 20.

    Spanish Clinical Trials Registry, 2020-001993-31: reec.aemps.es/reec/estudio/2020-001993-31.

    Not in our library

  21. 21.

    ClinicalTrials.gov, NCT04382066: https://clinicaltrials.gov/ct2/show/NCT04382066?term=plitidepsin&draw=2&rank=8.

    Not in our library

  22. 22.

    F. Amanat, K. M. White, L. Miorin, S. Strohmeier, M. McMahon, P. Meade, W.-C. Liu, R. A. Albrecht, V. Simon, L. Martinez-Sobrido, T. Moran, A. García-Sastre, F. Krammer, An In Vitro Microneutralization Assay for SARS-CoV-2 Serology and Drug Screening. Curr. Protoc. Microbiol. 58, e108 (2020 ).

    Not in our library10.1002/cpmc.108

  23. 23.

    A. Jacob, M. Vedaie, D. A. Roberts, D. C. Thomas, C. Villacorta-Martin, K.-D. Alysandratos, F. Hawkins, D. N. Kotton, Derivation of self-renewing lung alveolar epithelial type II cells from human pluripotent stem cells. Nat. Protoc. 14, 3303–3332 (2019 ).

    Not in our library10.1038/s41596-019-0220-0

  24. 24.

    M. Ghaedi, E. A. Calle, J. J. Mendez, A. L. Gard, J. Balestrini, A. Booth, P. F. Bove, L. Gui, E. S. White, L. E. Niklason, Human iPS cell-derived alveolar epithelium repopulates lung extracellular matrix. J. Clin. Invest. 123, 4950–4962 (2013 ).

    Not in our library10.1172/jci68793

  25. 25.

    R. A. Siemieniuk, J. J. Bartoszko, L. Ge, D. Zeraatkar, A. Izcovich, E. Kum, H. Pardo-Hernandez, B. Rochwerg, F. Lamontagne, M. A. Han, Q. Liu, A. Agarwal, T. Agoritsas, D. K. Chu, R. Couban, A. Darzi, T. Devji, B. Fang, C. Fang, S. A. Flottorp, F. Foroutan, M. Ghadimi, D. Heels-Ansdell, K. Honarmand, L. Hou, X. Hou, Q. Ibrahim, A. Khamis, B. Lam, M. Loeb, M. Marcucci, S. L. McLeod, S. Motaghi, S. Murthy, R. A. Mustafa, J. D. Neary, A. Qasim, G. Rada, I. B. Riaz, B. Sadeghirad, N. Sekercioglu, L. Sheng, A. Sreekanta, C. Switzer, B. Tendal, L. Thabane, G. Tomlinson, T. Turner, P. O. Vandvik, R. W. M. Vernooij, A. Viteri-García, Y. Wang, L. Yao, Z. Ye, G. H. Guyatt, R. Brignardello-Petersen, Drug treatments for covid-19: Living systematic review and network meta-analysis. BMJ 370, m2980 (2020 ).

    Not in our library10.1136/bmj.m2980

  26. 26.

    Y. Yokoyama, A. Briasoulis, H. Takagi, T. Kuno, Effect of remdesivir on patients with COVID-19: A network meta-analysis of randomized control trials. Virus Res. 288, 198137 (2020 ).

    Not in our library10.1016/j.virusres.2020.198137

  27. 27.
    SynergyFinder 2.0: visual analytics of multi-drug combination synergies · 2020
    No notice
  28. 28.

    P. Krastel, S. Roggo, M. Schirle, N. T. Ross, F. Perruccio, P. Aspesi Jr.., T. Aust, K. Buntin, D. Estoppey, B. Liechty, F. Mapa, K. Memmert, H. Miller, X. Pan, R. Riedl, C. Thibaut, J. Thomas, T. Wagner, E. Weber, X. Xie, E. K. Schmitt, D. Hoepfner, Nannocystin A: An Elongation Factor 1 Inhibitor from Myxobacteria with Differential Anti-Cancer Properties. Angew. Chem. Int. Ed. 54, 10149–10154 (2015 ).

    Not in our library10.1002/anie.201505069

  29. 29.

    J. D. Carelli, S. G. Sethofer, G. A. Smith, H. R. Miller, J. L. Simard, W. C. Merrick, R. K. Jain, N. T. Ross, J. Taunton, Ternatin and improved synthetic variants kill cancer cells by targeting the elongation factor-1A ternary complex. eLife 4, e10222 (2015 ).

    Not in our library10.7554/elife.10222

  30. 30.

    S. H. van den Worm, K. Knoops, J. C. Zevenhoven-Dobbe, C. Beugeling, Y. van der Meer, A. M. Mommaas, E. J. Snijder, Development and RNA-synthesizing activity of coronavirus replication structures in the absence of protein synthesis. J. Virol. 85, 5669–5673 (2011 ).

    Not in our library10.1128/jvi.00403-11

  31. 31.

    D. Bojkova, K. Klann, B. Koch, M. Widera, D. Krause, S. Ciesek, J. Cinatl, C. Münch, Proteomics of SARS-CoV-2-infected host cells reveals therapy targets. Nature 583, 469–472 (2020 ).

    Not in our library10.1038/s41586-020-2332-7

  32. 32.

    S. G. Sawicki, D. L. Sawicki, Coronavirus minus-strand RNA synthesis and effect of cycloheximide on coronavirus RNA synthesis. J. Virol. 57, 328–334 (1986 ).

    Not in our library10.1128/jvi.57.1.328-334.1986

  33. 33.

    S. G. Sawicki, D. L. Sawicki, S. G. Siddell, A contemporary view of coronavirus transcription. J. Virol. 81, 20–29 (2007 ).

    Not in our library10.1128/jvi.01358-06

  34. 34.

    S. G. Sawicki, D. L. Sawicki, Coronaviruses use discontinuous extension for synthesis of subgenome-length negative strands. Adv. Exp. Med. Biol. 380, 499–506 (1995 ).

    Not in our library10.1007/978-1-4615-1899-0_79

  35. 35.

    J. Delgado-Calle, N. Kurihara, E. G. Atkinson, J. Nelson, K. Miyagawa, C. M. Galmarini, G. D. Roodman, T. Bellido, Aplidin (plitidepsin) is a novel anti-myeloma agent with potent anti-resorptive activity mediated by direct effects on osteoclasts. Oncotarget 10, 2709–2721 (2019 ).

    Not in our library10.18632/oncotarget.26831

  36. 36.

    L. Yao, Aplidin PharmaMar. IDrugs 6, 246–250 (2003 ).

    Not in our library

  37. 37.

    P. E. Morande, S. R. Zanetti, M. Borge, P. Nannini, C. Jancic, R. F. Bezares, A. Bitsmans, M. González, A. L. Rodríguez, C. M. Galmarini, R. Gamberale, M. Giordano, The cytotoxic activity of Aplidin in chronic lymphocytic leukemia (CLL) is mediated by a direct effect on leukemic cells and an indirect effect on monocyte-derived cells. Invest. New Drugs 30, 1830–1840 (2012 ).

    Not in our library10.1007/s10637-011-9740-3

  38. 38.

    C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, N. C. Munshi, T. Hideshima, D. Chauhan, P. Aviles, G. Otero, G. Faircloth, M. V. Mateos, P. G. Richardson, F. Mollinedo, J. F. San-Miguel, K. C. Anderson, Aplidin, a marine organism-derived compound with potent antimyeloma activity in vitro and in vivo. Cancer Res. 68, 5216–5225 (2008 ).

    Not in our library10.1158/0008-5472.can-07-5725

  39. 39.

    R. Nalda-Molina, B. Valenzuela, A. Ramon-Lopez, B. Miguel-Lillo, A. Soto-Matos, J. J. Perez-Ruixo, Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects. Cancer Chemother. Pharmacol. 64, 97–108 (2009 ).

    Not in our library10.1007/s00280-008-0841-4

  40. 40.

    A. Soto-Matos, S. Szyldergemajn, S. Extremera, B. Miguel-Lillo, V. Alfaro, C. Coronado, P. Lardelli, E. Roy, C. S. Corrado, C. Kahatt, Plitidepsin has a safe cardiac profile: A comprehensive analysis. Mar. Drugs 9, 1007–1023 (2011 ).

    Not in our library10.3390/md9061007

  41. 41.

    R. Salazar, R. Plummer, A. Oaknin, A. Robinson, B. Pardo, A. Soto-Matos, A. Yovine, S. Szyldergemajn, A. H. Calvert, Phase I study of weekly plitidepsin as 1-hour infusion combined with carboplatin in patients with advanced solid tumors or lymphomas. Invest. New Drugs 29, 1406–1413 (2011 ).

    Not in our library10.1007/s10637-010-9488-1

  42. 42.

    R. L. Piekarz, A. R. Frye, J. J. Wright, S. M. Steinberg, D. J. Liewehr, D. R. Rosing, V. Sachdev, T. Fojo, S. E. Bates, Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin. Cancer Res. 12, 3762–3773 (2006 ).

    Not in our library10.1158/1078-0432.ccr-05-2095

  43. 43.

    M. H. Shah, P. Binkley, K. Chan, J. Xiao, D. Arbogast, M. Collamore, Y. Farra, D. Young, M. Grever, Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin. Cancer Res. 12, 3997–4003 (2006 ).

    Not in our library10.1158/1078-0432.ccr-05-2689

  44. 44.

    J. A. Maroun, K. Belanger, L. Seymour, S. Matthews, J. Roach, J. Dionne, D. Soulieres, D. Stewart, R. Goel, D. Charpentier, G. Goss, E. Tomiak, J. Yau, J. Jimeno, G. Chiritescu, Phase I study of Aplidine in a daily×5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115. Ann. Oncol. 17, 1371–1378 (2006 ).

    Not in our library10.1093/annonc/mdl165

  45. 45.
    Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection · 2020
    No notice
  46. 46.

    T. P. Sheahan, A. C. Sims, R. L. Graham, V. D. Menachery, L. E. Gralinski, J. B. Case, S. R. Leist, K. Pyrc, J. Y. Feng, I. Trantcheva, R. Bannister, Y. Park, D. Babusis, M. O. Clarke, R. L. Mackman, J. E. Spahn, C. A. Palmiotti, D. Siegel, A. S. Ray, T. Cihlar, R. Jordan, M. R. Denison, R. S. Baric, Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 9, eaal3653 (2017 ).

    Not in our library10.1126/scitranslmed.aal3653

  47. 47.

    E. S. Winkler, A. L. Bailey, N. M. Kafai, S. Nair, B. T. McCune, J. Yu, J. M. Fox, R. E. Chen, J. T. Earnest, S. P. Keeler, J. H. Ritter, L. I. Kang, S. Dort, A. Robichaud, R. Head, M. J. Holtzman, M. S. Diamond, SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat. Immunol. 21, 1327–1335 (2020 ).

    Not in our library10.1038/s41590-020-0778-2

  48. 48.

    D. Li, T. Wei, C. M. Abbott, D. Harrich, The unexpected roles of eukaryotic translation elongation factors in RNA virus replication and pathogenesis. Microbiol. Mol. Biol. Rev. 77, 253–266 (2013 ).

    Not in our library10.1128/mmbr.00059-12

  49. 49.
    The eEF1A Proteins: At the Crossroads of Oncogenesis, Apoptosis, and Viral Infections · 2015
    No notice
  50. 50.

    N. S. Heaton, N. Moshkina, R. Fenouil, T. J. Gardner, S. Aguirre, P. S. Shah, N. Zhao, L. Manganaro, J. F. Hultquist, J. Noel, D. Sachs, J. Hamilton, P. E. Leon, A. Chawdury, S. Tripathi, C. Melegari, L. Campisi, R. Hai, G. Metreveli, A. V. Gamarnik, A. García-Sastre, B. Greenbaum, V. Simon, A. Fernandez-Sesma, N. J. Krogan, L. C. F. Mulder, H. van Bakel, D. Tortorella, J. Taunton, P. Palese, I. Marazzi, Targeting Viral Proteostasis Limits Influenza Virus, HIV, and Dengue Virus Infection. Immunity 44, 46–58 (2016 ).

    Not in our library10.1016/j.immuni.2015.12.017

  51. 51.

    S. Sammaibashi, S. Yamayoshi, Y. Kawaoka, Strain-Specific Contribution of Eukaryotic Elongation Factor 1 Gamma to the Translation of Influenza A Virus Proteins. Front. Microbiol. 9, 1446 (2018 ).

    Not in our library10.3389/fmicb.2018.01446

  52. 52.
    The eukaryotic elongation factor 1A is critical for genome replication of the paramyxovirus respiratory syncytial virus. · 2014
    Not checked
  53. 53.

    X. Zhang, H. Shi, J. Chen, D. Shi, C. Li, L. Feng, EF1A interacting with nucleocapsid protein of transmissible gastroenteritis coronavirus and plays a role in virus replication. Vet. Microbiol. 172, 443–448 (2014 ).

    Not in our library10.1016/j.vetmic.2014.05.034

  54. 54.

    B. W. Neuman, J. S. Joseph, K. S. Saikatendu, P. Serrano, A. Chatterjee, M. A. Johnson, L. Liao, J. P. Klaus, J. R. Yates 3rd, K. Wüthrich, R. C. Stevens, M. J. Buchmeier, P. Kuhn, Proteomics analysis unravels the functional repertoire of coronavirus nonstructural protein 3. J. Virol. 82, 5279–5294 (2008 ).

    Not in our library10.1128/jvi.02631-07

  55. 55.

    A.-K. Reuschl, L. Thorne, L. Z. Alvarez, M. Bouhaddou, K. Obernier, M. Soucheray, J. Turner, J. Fabius, G. T. Nguyen, D. Swaney, R. Rosales, K. M. White, P. Aviles, I. T. Kirby, J. E. Melnyk, Y. Shi, Z. Zhang, K. Shokat, A. Garcia-Sastre, C. Jolly, G. J. Towers, N. J. Krogan, Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant. bioRxiv 427991 [preprint]. 24 January 2021.

    Not in our library10.1101/2021.01.24.427991

  56. 56.

    S. V. Rajkumar, Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am. J. Hematol. 95, 548–567 (2020 ).

    Not in our library10.1002/ajh.25791

  57. 57.

    New and Emerging Respiratory Virus Threats Advisory Group, NERVTAG meeting on SARS-CoV-2 variant under investigation VUI-202012/01 (18 December 2020); https://khub.net/documents/135939561/338928724/SARS-CoV-2+variant+under+investigation%2C+meeting+minutes.pdf/962e866b-161f-2fd5-1030-32b6ab467896?t=1608491166921.

    Not in our library

  58. 58.

    A. Rambaut et al., Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations (18 December 2020); https://virological.org/t/preliminary-genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-the-uk-defined-by-a-novel-set-of-spike-mutations/563.

    Not in our library

  59. 59.

    I. Spicka, E. M. Ocio, H. E. Oakervee, R. Greil, R. H. Banh, S.-Y. Huang, J. M. D’Rozario, M. A. Dimopoulos, S. Martínez, S. Extremera, C. Kahatt, V. Alfaro, A. M. Carella, N. Meuleman, R. Hájek, A. Symeonidis, C.-K. Min, P. Cannell, H. Ludwig, P. Sonneveld, M. V. Mateos, Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma. Ann. Hematol. 98, 2139–2150 (2019 ).

    Not in our library10.1007/s00277-019-03739-2

  60. 60.

    M. Leisch, A. Egle, R. Greil, Plitidepsin: A potential new treatment for relapsed/refractory multiple myeloma. Future Oncol. 15, 109–120 (2019 ).

    Not in our library10.2217/fon-2018-0492

  61. 61.

    T. C. Chou, Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev. 58, 621–681 (2006 ).

    Not in our library10.1124/pr.58.3.10

  62. 62.

    L. Riva, S. Yuan, X. Yin, L. Martin-Sancho, N. Matsunaga, L. Pache, S. Burgstaller-Muehlbacher, P. D. De Jesus, P. Teriete, M. V. Hull, M. W. Chang, J. F.-W. Chan, J. Cao, V. K.-M. Poon, K. M. Herbert, K. Cheng, T. H. Nguyen, A. Rubanov, Y. Pu, C. Nguyen, A. Choi, R. Rathnasinghe, M. Schotsaert, L. Miorin, M. Dejosez, T. P. Zwaka, K.-Y. Sit, L. Martinez-Sobrido, W.-C. Liu, K. M. White, M. E. Chapman, E. K. Lendy, R. J. Glynne, R. Albrecht, E. Ruppin, A. D. Mesecar, J. R. Johnson, C. Benner, R. Sun, P. G. Schultz, A. I. Su, A. García-Sastre, A. K. Chatterjee, K.-Y. Yuen, S. K. Chanda, Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature 586, 113–119 (2020 ).

    Not in our library10.1038/s41586-020-2577-1

  63. 63.

    L. Coughlan, A. C. Bradshaw, A. L. Parker, H. Robinson, K. White, J. Custers, J. Goudsmit, N. Van Roijen, D. H. Barouch, S. A. Nicklin, A. H. Baker, Ad5:Ad48 hexon hypervariable region substitutions lead to toxicity and increased inflammatory responses following intravenous delivery. Mol. Ther. 20, 2268–2281 (2012 ).

    Not in our library10.1038/mt.2012.162

  64. 64.

    L. Coughlan, S. Vallath, A. Saha, M. Flak, I. A. McNeish, G. Vassaux, J. F. Marshall, I. R. Hart, G. J. Thomas, In vivo retargeting of adenovirus type 5 to alphavbeta6 integrin results in reduced hepatotoxicity and improved tumor uptake following systemic delivery. J. Virol. 83, 6416–6428 (2009 ).

    Not in our library10.1128/jvi.00445-09

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