Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2022 Mar 30;13(4):520–523. doi: 10.1021/acsmedchemlett.2c00105

Phosphoramidate Prodrugs Continue to Deliver: The Journey of Remdesivir (GS-5734) from the Liver to Peripheral Blood Mononuclear Cells

Victoria C Yan 1,*
PMCID: PMC9014429  PMID: 35450350

Abstract

graphic file with name ml2c00105_0002.jpg

Remdesivir (GS-5734) is a monophenol, 2-ethylbutylalanine phosphoramidate prodrug of GS-441524 that is FDA-approved for the treatment of patients hospitalized for COVID-19. Despite showing strong, broad-spectrum antiviral activity in preclinical models, the clinical efficacy of remdesivir is mixed. This work highlights the pharmacodynamic discordance of remdesivir between humans and non-human primates, thereby demonstrating that non-human primate disease models overestimate the therapeutic efficacy of phosphoramidate prodrugs.

Keywords: Remdesivir, GS-441524, prodrug, antiviral nucleoside, non-human primates

At the heart of all therapeutics programs lies one basic question which all teams must confront: Am I designing drugs to treat model species or humans? Evaluating the activity of superbly potent and selective modulators of a target in preclinical species is often a straightforward aspect of the drug development process. However, it is the extrapolation of preclinical efficacy data to humans that poses a greater hurdle. It is especially challenging to anticipate in vivo drug distribution in humans when the inhibitor is a prodrug, is subject to metabolic transformations that vary across species, and has an intracellular target.

Remdesivir (RDV; GS-5734, Veklury) is a monophoenol, 2-ethylbutylalanine phosphoramidate (McGuigan) prodrug of its parent nucleoside, GS-441524, and is FDA-approved for the treatment of COVID-19. The efficacy of RDV in patients hospitalized for COVID-19 is mixed, with only one large, double-blind, randomized control trial (RCT) showing shorter time-to-recovery with RDV treatment;1 all other RCTs have demonstrated no statistically significant improvement with RDV treatment related to recovery, symptomatic improvement, or decrease in viral titers compared to placebo control.2−5 In patients with mild/moderate COVID-19 treated with intravenous RDV in the outpatient setting, the efficacy of RDV is unambiguous: 87% lower risk of hospitalization or death compared to placebo.6 Prior to being repurposed for COVID-19, RDV was clinically evaluated for the treatment of Ebola, in which it failed to demonstrate significant improvements to survival or decreases in viral load compared to other treatments evaluated.7 That RDV failed to deliver against Ebola is particularly striking, considering the profound benefit it provided in rhesus models of Ebola: 100% survival in a lethal disease and decreases in viral titers most apparent in the highest dosing group.8

A recent piece by Mackman describes the history of RDV’s development and pedestals the phosphoramidate prodrug strategy—as exemplified by RDV—for non-hepatic diseases like COVID-19.9 In reference to the decision to develop RDV over its parent nucleoside, GS-441524,10 Mackman argues that nucleoside phosphoramidate prodrugs enable more efficient intracellular delivery of the corresponding bioactive nucleoside triphosphate (NTP) due improved cellular permeability and nucleoside kinase bypass—a potentially rate-limiting but requisite step in the bioconversion of nucleoside but not nucleotide analogues. In support of this thesis, he cites in vitro potency differences between RDV and GS-441524 across several viruses and the ability for RDV to efficiently deliver bioactive NTP to the lungs at higher levels than that achieved by GS-441524 in non-human primate models of viral disease.11,12

It is not the experimental results, but rather the interpretation of these data in the context of RDV’s disposition in humans—that is the subject of debate. I and my co-workers have identified the erroneous assumptions made at the in vitro and in vivo levels of RDV’s development which foreshadowed the therapeutic inefficacy of RDV in Ebola and hospitalized COVID-19.13 The uniquely high expression of carboxylesterase 1 (CES1) and cathepsin A (CTSA) in hepatocytes that facilitates the success of the success of phosphoramidate prodrugs like sofosbuvir for hepatitis C14 subverts the therapeutic efficacy of RDV in non-hepatic diseases like COVID-19 and Ebola. To circumvent RDV’s design flaws, I and my co-workers have advocated for developing GS-441524 for diseases such as COVID-1910—predicating our rationale on its established efficacy against multiple RNA viruses and safety profile in multiple species.15−18 Mackman acknowledges the high hepatic expression of CES1/CTSA but points to the ability for RDV to deposit NTP more efficiently in peripheral blood mononuclear cells (PBMCs) and the lungs of non-human primates than GS-441524 as support for applying phosphoramidate prodrugs like RDV to non-hepatic, respiratory diseases. However, two important questions remain unaddressed by Mackman and co-workers: (1) In the case of COVID-19, to what extent is bioactive NTP released in pneumocytes, the primary site of SARS-CoV-2 infection? (2) Are the pharmacodynamics of RDV observed in non-human primates consistent in humans?

Current technical limitations preclude examining the cell-type-specific pharmacodynamics that would be required to directly answer the first question. However, enzyme expression data from single-cell RNA sequencing (scRNA-seq) and immunohistochemistry show that CES1/CTSA are most highly expressed in lung macrophages, rather than pneumocytes.10,19 In contrast, pneumocytes exhibit moderate expression of nucleoside kinases, like adenosine kinase (ADK), that are involved in the bioconversion of GS-441524 toward the bioactive NTP. In addition to these expression data, a head-to-head challenge experiment between GS-441524 (20 mg/kg IV) and RDV (10/5 mg/kg IV) in an African green monkey model of COVID-19 shows similar—if not equivalent—reductions in lung viral titers compared to untreated controls despite higher levels of bioactive NTP detected in the lungs after RDV dosing (Gilead Sciences, personal communication, October 2020). Infection dynamics of SARS-CoV-2 in the African green monkey model have been characterized histologically and by scRNA-seq, which expectedly show that pneumocytes are the main site of productive virus replication.20 Given the direct relationship between NTP formation and antiviral activity,21 it is apparent that differences in whole lung levels of NTP are insufficient to explain the same viral titer reductions in this non-human primate model. Early studies examining the cellular composition of the lung across select species have shown that pneumocytes comprise approximately 16% of total lung cells in humans, possess a relatively low cell volume compared to other lung cell types, and comprise approximately 7% of the alveolar surface (Figure 1a).22 These values are consistent across species examined, including in non-human primates (baboons). The low surface area coverage by pneumocytes coupled with the equivalent daily decrease in SARS-CoV-2 viral titers between RDV- and GS-441524 treated African green monkeys—despite higher total lung levels of bioactive NTP in RDV-treated animals—implicates the significance of cell-type-specific differences in prodrug bioactivation.

Figure 1.

Figure 1

Open in a new tab

Species differences in remdesivir pharmacodynamics between humans and nonhuman primates. (A) Cellular composition of the lung is similar across species. Data are replotted from ref (22). Alveolar type II cells = pneumocytes. (B) In vitro formation of bioactive NTP (GS-443902) following 1 μM incubation of RDV in freshly harvested white cell types from human (black) and rhesus (white). Data replotted form RDV regulatory filing data (Study AD-399-2015) and are the mean ± SD of two independent experiments for PBMCs and monocytes and six independent experiments for macrophages from different donors. For all cell types, levels of bioactive NTP are significantly higher in human- versus rhesus-derived cells (unpaired t test with Holm-Sidak correction). (C) In vivo C24 levels of bioactive NTP in PBMCs following IV administration of RDV at allometrically adjusted doses in non-human primates and humans replotted form RDV regulatory filing data (Section 2.6.4—Pharmacokinetics and Written Summary for Remdesivir (GS-5734)). The T1/2 of the bioactive NTP in rhesus and human white cells is reportedly similar (≥14 h), ref (8).

In regard to the second question: there is currently insufficient clinical data to determine the pharmacodynamics of RDV in human lungs. While comparative studies between non-human primates and humans could perhaps be conducted by examining levels of bioactive NTP in bronchial alveolar lavage fluid, in COVID-19 patients treated with RDV who then received a lung transplant, or in autopsies of COVID-19 patients treated with RDV, there are currently no published data for these circumstances. However, there are extensive data on the interspecies pharmacodynamics of RDV in PBMCs, a cell type implicated in Ebola virus disease, which can provide insight into species differences in RDV catabolism. Mackman cites the ability for intravenous RDV (10 or 5 mg/kg) to efficiently deliver the bioactive NTP to PBMCs at micromolar concentrations in non-human primates which, coupled with the large volumes of distribution in non-human primates and humans, suggested that the bioactive NTP could be formed in other non-hepatic tissues like the lungs.8,9 Our main point of contention is not whether the bioactive NTP can be formed in non-hepatic tissue but rather whether sufficiently high levels of bioactive NTP can be formed in these tissues in humans without concomitantly high bioactivation in the liver that would result in toxicity. Despite the similarly high calculated volumes of distribution in non-human primates and humans, empirical evidence in humans supports species differences in RDV catabolism for which non-human primate models fail to account. Gilead’s published works have shown that non-human primate livers do not appear to metabolize McGuigan prodrugs as efficiently as those of humans, as evidenced by the lowest levels of bioactive NTP following oral administration of sofosbuvir to non-human primates compared to other species23 and by the absence of ALT/AST elevations in non-human primates intravenously administered 10 mg/kg RDV for 12 days.8 In contrast, healthy humans intravenously administered the allometrically adjusted dose of 150 mg RDV experienced dose-duration-dependent transaminitis after 7 and 14 days (2/8 and 6/8 participants, respectively).13,24 Consequently, the efficiency of NTP formation by RDV in PBMCs and other tissue like the lungs is impacted by species differences in hepatic metabolism. This is most clearly demonstrated by comparing levels of bioactive NTP in human and rhesus PBMCs in vitro and in vivo. Whereas levels of bioactive NTP are 4-fold higher in human compared to rhesus PBMCs when subject to continuous, supraphysiological concentrations of RDV for 2 h in vitro, this interspecies trend reverses in vivo: at similar plasmatic exposures, levels of bioactive NTP are significantly higher in rhesus (10 mg/kg) compared to humans (150 mg; Figure 1b vs c). Two conclusions arise from this observation: (1) Insufficient levels of bioactive NTP were formed in humans treated with the standard clinical dose of RDV for Ebola. (2) The up-dosing in humans that would be required to achieve the profound therapeutic effects in non-human primate models of Ebola cannot be achieved without concomitantly high levels of prodrug bioactivation in the liver that elicits hepatotoxicity. Both of these conclusions are supported by the starkly divergent therapeutic outcomes between humans and non-human primate models of Ebola: whereas RDV failed to reduce plasma viral titers or improve survival outcomes in humans,7 10 mg/kg intravenous RDV for 12 days in a rhesus model of Ebola yielded 100% (6/6) survival and significant decrease in viral titers in a disease model that resulted in 100% lethality by day 14 of the 28-day study.8 Considering these data with respect to the second question: differences in PBMC NTP levels and transaminase elevations suggest that the pharmacodynamics of RDV in non-human primates and humans are discordant. As a result, non-human primate models of non-hepatic diseases overestimate the therapeutic efficacy of McGuigan prodrugs like RDV in humans. If RDV were being developed as a broad-spectrum antiviral treatment for non-human primates, then the argumentation presented by Mackman and co-workers would suffice. But because RDV and emerging phosphoramidate prodrugs are primarily intended to treat humans, identifying interspecies metabolic differences to better inform the pharmacodynamic and therapeutic activity of this prodrug class in humans is imperative.

Views expressed in this viewpoint are those of the author and not necessarily the views of the ACS.

The author declares no competing financial interest.

References

  1. Beigel J. H.; Tomashek K. M.; Dodd L. E.; Mehta A. K.; Zingman B. S.; Kalil A. C.; Hohmann E.; Chu H. Y.; Luetkemeyer A.; Kline S.; Lopez de Castilla D.; Finberg R. W.; Dierberg K.; Tapson V.; Hsieh L.; Patterson T. F.; Paredes R.; Sweeney D. A.; Short W. R.; Touloumi G.; Lye D. C.; Ohmagari N.; Oh M.-d.; Ruiz-Palacios G. M.; Benfield T.; Fatkenheuer G.; Kortepeter M. G.; Atmar R. L.; Creech C. B.; Lundgren J.; Babiker A. G.; Pett S.; Neaton J. D.; Burgess T. H.; Bonnett T.; Green M.; Makowski M.; Osinusi A.; Nayak S.; Lane H. C. for the ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19-Final report. N. Engl. J. Med. 2020, 383, 1813–1826. 10.1056/NEJMoa2007764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Wang Y.; Zhang D.; Du G.; Du R.; Zhao J.; Jin Y.; Fu S.; Gao L.; Cheng Z.; Lu Q.; Hu Y.; Luo G.; Wang K.; Lu Y.; Li H.; Wang S.; Ruan S.; Yang C.; Mei C.; Wang Y.; Ding D.; Wu F.; Tang X.; Ye X.; Ye Y.; Liu B.; Yang J.; Yin W.; Wang A.; Fan G.; Zhou F.; Liu Z.; Gu X.; Xu J.; Shang L.; Zhang Y.; Cao L.; Guo T.; Wan Y.; Qin H.; Jiang Y.; Jaki T.; Hayden F. G.; Horby P. W.; Cao B.; Wang C. Remdesivir in Adults with Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial. Lancet 2020, 395 (10236), 1569–1578. 10.1016/S0140-6736(20)31022-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N. Engl. J. Med. 2021, 384, 497–511. 10.1056/NEJMoa2023184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ohl M. E.; Miller D. R.; Lund B. C.; Kobayashi T.; Richardson Miell K.; Beck B. F.; Alexander B.; Crothers K.; Vaughan Sarrazin M. S. Association of Remdesivir Treatment with Survival and Length of Hospital Stay among US Veterans Hospitalized with COVID-19. JAMA Netw. Open 2021, 4 (7), e2114741. 10.1001/jamanetworkopen.2021.14741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Ali K.; Azher T.; Baqi M.; Binnie A.; Borgia S.; Carrier F. M.; Cavayas Y. A.; Chagnon N.; Cheng M. P.; Conly J.; Costiniuk C.; Daley P.; Daneman N.; Douglas J.; Downey C.; Duan E.; Duceppe E.; Durand M.; English S.; Farjou G.; Fera E.; Fontela P.; Fowler R.; Fralick M.; Geagea A.; Grant J.; Harrison L. B.; Havey T.; Hoang H.; Kelly L. E.; Keynan Y.; Khwaja K.; Klein G.; Klein M.; Kolan C.; Kronfli N.; Lamontagne F.; Lau R.; Fralick M.; Lee T. C.; Lee N.; Lim R.; Longo S.; Lostun A.; MacIntyre E.; Malhamé I.; Mangof K.; McGuinty M.; Mergler S.; Munan M. P.; Murthy S.; O’Neil C.; Ovakim D.; Papenburg J.; Parhar K.; Parvathy S. N.; Patel C.; Perez-Patrigeon S.; Pinto R.; Rajakumaran S.; Rishu A.; Roba-Oshin M.; Rushton M.; Saleem M.; Salvadori M.; Scherr K.; Schwartz K.; Semret M.; Silverman M.; Singh A.; Sligl W.; Smith S.; Somayaji R.; Tan D. H. S.; Tobin S.; Todd M.; Tran T.-V.; Tremblay A.; Tsang J.; Turgeon A.; Vakil E.; Weatherald J.; Yansouni C.; Zarychanski R. Remdesivir for the Treatment of Patients in Hospital with COVID-19 in Canada: A Randomized Controlled Trial. Can. Med. Assoc. J. 2022, 194, E242. 10.1503/cmaj.211698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gottlieb R. L.; Vaca C. E.; Paredes R.; Mera J.; Webb B. J.; Perez G.; Oguchi G.; Ryan P.; Nielsen B. U.; Brown M.; Hidalgo A.; Sachdeva Y.; Mittal S.; Osiyemi O.; Skarbinski J.; Juneja K.; Hyland R. H.; Osinusi A.; Chen S.; Camus G.; Abdelghany M.; Davies S.; Behenna-Renton N.; Duff F.; Marty F. M.; Katz M. J.; Ginde A. A.; Brown S. M.; Schiffer J. T.; Hill J. A. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N. Engl. J. Med. 2022, 386, 305–315. 10.1056/NEJMoa2116846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Mulangu S.; Dodd L. E.; Davey R. T.; Tshiani Mbaya O.; Proschan M.; Mukadi D.; Lusakibanza Manzo M.; Nzolo D.; Tshomba Oloma A.; Ibanda A.; Ali R.; Coulibaly S.; Levine A. C.; Grais R.; Diaz J.; Lane H. C.; Muyembe-Tamfum J.-J.; A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics. N. Engl. J. Med. 2019, 381 (24), 2293–2303. 10.1056/NEJMoa1910993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Warren T. K.; Jordan R.; Lo M. K.; Ray A. S.; Mackman R. L.; Soloveva V.; Siegel D.; Perron M.; Bannister R.; Hui H. C.; Larson N.; Strickley R.; Wells J.; Stuthman K. S.; Van Tongeren S. A.; Garza N. L.; Donnelly G.; Shurtleff A. C.; Retterer C. J.; Gharaibeh D.; Zamani R.; Kenny T.; Eaton B. P.; Grimes E.; Welch L. S.; Gomba L.; Wilhelmsen C. L.; Nichols D. K.; Nuss J. E.; Nagle E. R.; Kugelman J. R.; Palacios G.; Doerffler E.; Neville S.; Carra E.; Clarke M. O.; Zhang L.; Lew W.; Ross B.; Wang Q.; Chun K.; Wolfe L.; Babusis D.; Park Y.; Stray K. M.; Trancheva I.; Feng J. Y.; Barauskas O.; Xu Y.; Wong P.; Braun M. R.; Flint M.; McMullan L. K.; Chen S.-S.; Fearns R.; Swaminathan S.; Mayers D. L.; Spiropoulou C. F.; Lee W. A.; Nichol S. T.; Cihlar T.; Bavari S. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016, 531, 381–385. 10.1038/nature17180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Mackman R. L. Phosphoramidate Prodrugs Continue to Deliver, The Journey of Remdesivir (GS-5734) from RSV to SARS-CoV-2. ACS Med. Chem. Lett. 2022, 13, 338–347. 10.1021/acsmedchemlett.1c00624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Yan V. C.; Muller F. L. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. ACS Med. Chem. Lett. 2020, 11, 1361–1366. 10.1021/acsmedchemlett.0c00316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Williamson B. N.; Feldmann F.; Schwarz B.; Meade-White K.; Porter D. P.; Schulz J.; Van Doremalen N.; Leighton I.; Yinda C. K.; Pérez-Pérez L.; Okumura A.; Lovaglio J.; Hanley P. W.; Saturday G.; Bosio C. M.; Anzick S.; Barbian K.; Cihlar T.; Martens C.; Scott D. P.; Munster V. J.; De Wit E. Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2. Nature 2020, 585 (7824), 273–276. 10.1038/s41586-020-2423-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mackman R. L.; Hui H. C.; Perron M.; Murakami E.; Palmiotti C.; Lee G.; Stray K.; Zhang L.; Goyal B.; Chun K.; Byun D.; Siegel D.; Simonovich S.; Du Pont V.; Pitts J.; Babusis D.; Vijjapurapu A.; Lu X.; Kim C.; Zhao X.; Chan J.; Ma B.; Lye D.; Vandersteen A.; Wortman S.; Barrett K. T.; Toteva M.; Jordan R.; Subramanian R.; Bilello J. P.; Cihlar T. Prodrugs of a 1′-CN-4-Aza-7,9-Dideazaadenosine C -Nucleoside Leading to the Discovery of Remdesivir (GS-5734) as a Potent Inhibitor of Respiratory Syncytial Virus with Efficacy in the African Green Monkey Model of RSV. J. Med. Chem. 2021, 64 (8), 5001–5017. 10.1021/acs.jmedchem.1c00071. [DOI] [PubMed] [Google Scholar]
  13. Yan V. C.; Muller F. L. Why Remdesivir Failed: Preclinical Assumptions Overestimate the Clinical Efficacy of Remdesivir for COVID-19 and Ebola. Antimicrob. Agents Chemother. 2021, 65 (10), e0111721 10.1128/AAC.01117-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sofia M. J.; Bao D.; Chang W.; Du J.; Nagarathnam D.; Rachakonda S.; Reddy P. G.; Ross B. S.; Wang P.; Zhang H.-R.; Bansal S.; Espiritu C.; Keilman M.; Lam A. M.; Steuer H. M. M.; Niu C.; Otto M. J.; Furman P. A. Discovery of a β- d −2′-Deoxy-2′-α-Fluoro-2′-β-C-Methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus. J. Med. Chem. 2010, 53 (19), 7202–7218. 10.1021/jm100863x. [DOI] [PubMed] [Google Scholar]
  15. Wang A. Q.; Hagen N. R.; Padilha E. C.; Yang M.; Shah P.; Catherine Z.; Huang W.; Terse P.; Sanderson P.; Zheng W.; Xu X. Preclinical Pharmacokinetics and In Vitro Properties of GS-441524, A Potential Oral Drug Candidate for COVID-19 Treatment. bioRxiv Preprint 2022, 2022.02.07.478848 10.1101/2022.02.07.478848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li Y.; Cao L.; Li G.; Cong F.; Li Y.; Sun J.; Luo Y.; Chen G.; Li G.; Wang P.; Xing F.; Ji Y.; Zhao J.; Zhang Y.; Guo D.; Zhang X. Remdesivir Metabolite GS-441524 Effectively Inhibits SARS-CoV-2 Infection in Mouse Models. J. Med. Chem. 2022, 65 (4), 2785–2793. 10.1021/acs.jmedchem.0c01929. [DOI] [PubMed] [Google Scholar]
  17. Pedersen N. C.; Perron M.; Bannasch M.; Montgomery E.; Murakami E.; Liepnieks M.; Liu H. Efficacy and Safety of the Nucleoside Analog GS-441524 for Treatment of Cats with Naturally Occurring Feline Infectious Peritoniti. J. Feline Med. Surg. 2019, 21 (4), 271–281. 10.1177/1098612X19825701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dickinson P. J.; Bannasch M.; Thomasy S. M.; Murthy V. D.; Vernau K. M.; Liepnieks M.; Montgomery E.; Knickelbein K. E.; Murphy B.; Pedersen N. C. Antiviral Treatment Using the Adenosine Nucleoside Analogue GS-441524 in Cats with Clinically Diagnosed Neurological Feline Infectious Peritonitis. J. Vet. Int. Med. 2020, 34, 1587–1593. 10.1111/jvim.15780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Li R.; Liclican A.; Xu Y.; Pitts J.; Niu C.; Zhang J.; Kim C.; Zhao X.; Soohoo D.; Babusis D.; Yue Q.; Ma B.; Murray B. P.; Subramanian R.; Xie X.; Zou J.; Bilello J. P.; Li L.; Schultz B. E.; Sakowicz R.; Smith B. J.; Shi P.-Y.; Murakami E.; Feng J. Y. Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells. Antimicrob. Agents Chemother. 2021, 65 (9), e00602-21 10.1128/AAC.00602-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Speranza E.; Williamson B. N.; Feldmann F.; Sturdevant G. L.; Pérez-Pérez L.; Meade-White K.; Smith B. J.; Lovaglio J.; Martens C.; Munster V. J.; Okumura A.; Shaia C.; Feldmann H.; Best S. M.; De Wit E. Single-Cell RNA Sequencing Reveals SARS-CoV-2 Infection Dynamics in Lungs of African Green Monkeys. Sci. Transl. Med. 2021, 13 (578), eabe8146. 10.1126/scitranslmed.abe8146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pruijssers A. J.; George A. S.; Schafer A.; Leist S. R.; Gralinksi L. E.; Dinnon K. H.; Yount B. L.; Agostini M. L.; Stevens L. J.; Chappell J. D.; Lu X.; Hughes T. M.; Gully K.; Martinez D. R.; Brown A. J.; Graham R. L.; Perry J. K.; Du Pont V.; Pitts J.; Ma B.; Babusis D.; Murakami E.; Feng J. Y.; Bilello J. P.; Porter D. P.; Cihlar T.; Baric R. S.; Denison M. R.; Sheahan T. P. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Rep. 2020, 32, 107940. 10.1016/j.celrep.2020.107940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Crapo J. D.; Barry B. E.; Gehr P.; Bachofen M.; Weibel E. R. Cell Number and Cell Characteristics of the Normal Human Lung. Am. Rev. Respir. Dis. 1982, 125 (6), 740–745. 10.1164/arrd.1982.125.6.740. [DOI] [PubMed] [Google Scholar]
  23. Wang T.; Babusis D.; Park Y.; Niu C.; Kim C.; Zhao X.; Lu B.; Ma B.; Muench R. C.; Sperger D.; Ray A. S.; Murakami E. Species Differences in Liver Accumulation and Metabolism of Nucleotide Prodrug Sofosbuvir. Drug Metab. Pharmacokinet. 2020, 35 (3), 334–340. 10.1016/j.dmpk.2020.04.333. [DOI] [PubMed] [Google Scholar]
  24. Humeniuk R.; Mathias A.; Cao H.; Osinusi A.; Shen G.; Chng E.; Ling J.; Vu A.; German P. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin. Transl. Sci. 2020, 13 (5), 896–906. 10.1111/cts.12840. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES