Tomas Cihlar (born 1967)

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Gilead Drug Remdesivir Is a Rare Example of Foresight in the Coronavirus Pandemic

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Dove sta andando la ricerca di Gilead? Lo abbiamo chiesto al capo della ricerca virologica

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Tomáš Cihlář

Tomáš Cihlář


Born

1967 (age 54–55)

Plzeň, Czechoslovakia (now Czech Republic)

Nationality

Czech

Alma mater

University of Chemistry and Technology, Prague

Occupation

Biochemist, virologist

Known for

Remdesivir, tenofovir disoproxil

Tomáš Cihlář (born 1967) is a Czech biochemist known for his role in the development of remdesivir. A specialist in virology, Cihlář holds the positions of Senior Director, Biology, and Vice-President at American pharmaceutical company Gilead Sciences. As a student, Cihlář assisted fellow biochemist Antonín Holý in developing Viread, the primary drug used to fight HIV infection.[1]

Education[edit]

Cihlář graduated from the University of Chemistry and Technology, Prague, majoring in fermentation chemistry and bioengineering under the tutelage of Jan Páca and Vladimír Jirků. He completed his postgraduate studies at the Institute of Organic Chemistry and Biochemistry of the ASCR under Ivan Rosenberg and Ivan Votruba. In 1994 he obtained the title of Candidate of Sciences and was engaged in the research of antiviral agents under the tutelage of Antonín Holý.

That same year, he traveled to the United States for a postdoctoral fellowship with Gilead Sciences, where as researcher he worked on the development of antiviral nucleotide analogs including tenofovir disoproxil fumarate, which, marketed as Viread, has become a primary drug in the fight against HIV infection.[2]

Career[edit]

At Gilead, leading a team of hundreds of scientists working on new substances for the treatment of HIV, viral hepatitis B, respiratory infections and other viral diseases such as Ebola, MERS, and dengue fever, Cihlář is as of 2020 responsible for biological research on HIV and respiratory viruses. On a number of these projects, he continues to work closely with scientists from the Institute of Organic Chemistry and Biochemistry, particularly Zdeněk Havlas and Zdeněk Hostomský,[3] and with the Radim Nencka Group,[4] which develops compounds capable of stopping the replication of important human pathogens by blocking the remodeling of cell membranes induced by these viruses.[5]

Cihlář is engaged in ongoing research into HIV inhibitors that target the enzyme integrase and prevent the formation of viral capsids.[6] Recently, these entail low molecular weight agonists of TLR7 (toll-like receptor 7).[7] TLR7 receptors recognize single-stranded RNA in endosomes and play a role in innate antiviral immunity. Such substances should help eliminate the HIV reservoir in T-lymphocytes and completely cure HIV patients.[5]

In 2006, Cihlář received a William Prusoff Young Investigator Lecture Award from the International Society for Antiviral Research for his work on antiviral nucleotide analogs. He has patented dozens of novel inventions.[8]

Remdesivir[edit]

Also at Gilead, Cihlář is one of the company's lead researchers in the development of remdesivir,[9][10] originally intended for treatment of Ebola. However, the Ebola epidemic ended before the new drug could be tested. Remdesivir briefly showed considerable promise in treating COVID-19 infection;[11] in April 2020 the company provided 5,000 doses for experimental use in China[12] and four hundred patients in 50 other countries.[13] Remdesivir was used to treat the first confirmed case of coronavirus in the U.S.[14][n 1]

In North Bethesda, Maryland, the National Institute of Allergy and Infectious Diseases conducted a trial involving 1,063 patients, some of whom were given the drug while others received a placebo. "The data shows remdesivir has a clear-cut, significant, positive effect in diminishing the time to recovery", NIAID director Dr. Anthony Fauci said.[15] "What it has proven is a drug can block this virus," Fauci added, "opening the door to the fact that we now have the capability of treating patients."[16] A week earlier, the WHO released, then retracted results from remdesivir trials in China finding the drug had "absolutely no benefit" for coronavirus patients.[17] Fauci stated that the WHO report was "not an adequate study", citing the fact that the trials were halted early due to a lack of volunteers.[18]

In early June 2020 it was reported that AstraZeneca, a British-Swedish multinational pharmaceutical and biopharmaceutical company headquartered in Cambridge, England, was pursuing a merger with Gilead due to a shared interest in the potential of remdesivir.[19]

In September 2020, following a review of purported evidence, the WHO’s guidelines committee issued a statement that there was no evidence of benefit, adding that Covid patients may be better off without it.[20] The statement, published in The BMJ, concludes, "Any beneficial effects of remdesivir, if they do exist, are likely to be small and the possibility of important harm remains.”[21] In October 2020, recognizing his involvement in the development of Remdesivir, which was thought potentially effective in treating Covid-19, Czech president Miloš Zeman awarded Cihlář the country's Silver Medal of Merit.[22]

In April 2021 Cihlář discussed the possibility of marketing remdesivir in pill form.[23]

References[edit]

Notes[edit]

Citations[edit]

Further reading[edit]




2017

https://pubmed.ncbi.nlm.nih.gov/28124907/

J Med Chem




. 2017 Mar 9;60(5):1648-1661. doi: 10.1021/acs.jmedchem.6b01594. Epub 2017 Feb 14.

Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses

Dustin Siegel 1, Hon C Hui 1, Edward Doerffler 1, Michael O Clarke 1, Kwon Chun 1, Lijun Zhang 1, Sean Neville 1, Ernest Carra 1, Willard Lew 1, Bruce Ross 1, Queenie Wang 1, Lydia Wolfe 1, Robert Jordan 1, Veronica Soloveva 2, John Knox 1, Jason Perry 1, Michel Perron 1, Kirsten M Stray 1, Ona Barauskas 1, Joy Y Feng 1, Yili Xu 1, Gary Lee 1, Arnold L Rheingold 3, Adrian S Ray 1, Roy Bannister 1, Robert Strickley 1, Swami Swaminathan 1, William A Lee 1, Sina Bavari 2, Tomas Cihlar 1, Michael K Lo 4, Travis K Warren 2, Richard L Mackman 1

Affiliations collapse

Affiliations

  • 1

  • Gilead Sciences, Inc. , Foster City, California 94404, United States.

  • 2

  • United States Army Medical Research Institute of Infectious Diseases (USAMRIID) , Frederick, Maryland 21702, United States.

  • 3

  • University of California-San Diego , San Diego, California 92093, United States.

  • 4

  • Centers for Disease Control and Prevention , Atlanta, Georgia 30333, United States.

Free PMC article


https://pubmed.ncbi.nlm.nih.gov/28659436/

Sci Transl Med




. 2017 Jun 28;9(396):eaal3653. doi: 10.1126/scitranslmed.aal3653.

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Timothy P Sheahan 1, Amy C Sims 1, Rachel L Graham 1, Vineet D Menachery 1, Lisa E Gralinski 1, James B Case 2, Sarah R Leist 1, Krzysztof Pyrc 3, Joy Y Feng 4, Iva Trantcheva 4, Roy Bannister 4, Yeojin Park 4, Darius Babusis 4, Michael O Clarke 4, Richard L Mackman 4, Jamie E Spahn 4, Christopher A Palmiotti 4, Dustin Siegel 4, Adrian S Ray 4, Tomas Cihlar 4, Robert Jordan 4, Mark R Denison 5, Ralph S Baric 6

Affiliations expand

Free PMC article


Affiliations

  • 1

  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

  • 2

  • Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

  • 3

  • Department of Microbiology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Krakow, Poland.

  • 4

  • Gilead Sciences Inc., Foster City, CA 94404, USA.

  • 5

  • Division of Infectious Diseases, Department of Pediatrics and Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.

  • 6

  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. mark.denison@vanderbilt.edu rbaric@email.unc.edu.




https://pubmed.ncbi.nlm.nih.gov/29511076/

mBio




. 2018 Mar 6;9(2):e00221-18. doi: 10.1128/mBio.00221-18.

Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Maria L Agostini # 1, Erica L Andres # 2, Amy C Sims 3, Rachel L Graham 3, Timothy P Sheahan 3, Xiaotao Lu 2, Everett Clinton Smith 2 4, James Brett Case 1, Joy Y Feng 5, Robert Jordan 5, Adrian S Ray 5, Tomas Cihlar 5, Dustin Siegel 5, Richard L Mackman 5, Michael O Clarke 5, Ralph S Baric 6, Mark R Denison 7 2

Affiliations collapse

Affiliations

  • 1

  • Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

  • 2

  • Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

  • 3

  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

  • 4

  • Department of Biology, the University of the South, Sewanee, Tennessee, USA.

  • 5

  • Gilead Sciences, Inc., Foster City, California, USA.

  • 6

  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA rbaric@email.unc.edu mark.denison@vanderbilt.edu.

  • 7

  • Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA rbaric@email.unc.edu mark.denison@vanderbilt.edu.

#

Contributed equally.

Free PMC article


https://pubmed.ncbi.nlm.nih.gov/31142680/

Sci Transl Med




. 2019 May 29;11(494):eaau9242. doi: 10.1126/scitranslmed.aau9242.

Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge

Michael K Lo 1, Friederike Feldmann 2, Joy M Gary 1, Robert Jordan 3, Roy Bannister 3, Jacqueline Cronin 4, Nishi R Patel 1, John D Klena 1, Stuart T Nichol 1, Tomas Cihlar 3, Sherif R Zaki 1, Heinz Feldmann 4, Christina F Spiropoulou 1, Emmie de Wit 5

Affiliations expand

Free PMC article

Abstract

Nipah virus is an emerging pathogen in the Paramyxoviridae family. Upon transmission of Nipah virus from its natural reservoir, Pteropus spp. fruit bats, to humans, it causes respiratory and neurological disease with a case-fatality rate about 70%. Human-to-human transmission has been observed during Nipah virus outbreaks in Bangladesh and India. A therapeutic treatment for Nipah virus disease is urgently needed. Here, we tested the efficacy of remdesivir (GS-5734), a broad-acting antiviral nucleotide prodrug, against Nipah virus Bangladesh genotype in African green monkeys. Animals were inoculated with a lethal dose of Nipah virus, and a once-daily intravenous remdesivir treatment was initiated 24 hours later and continued for 12 days. Mild respiratory signs were observed in two of four treated animals, whereas all control animals developed severe respiratory disease signs. In contrast to control animals, which all succumbed to the infection, all remsdesivir-treated animals survived the lethal challenge, indicating that remdesivir represents a promising antiviral treatment for Nipah virus infection.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.





https://pubmed.ncbi.nlm.nih.gov/31233808/


Antiviral Res




. 2019 Sep;169:104541. doi: 10.1016/j.antiviral.2019.104541. Epub 2019 Jun 21.

Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase

Ariane J Brown 1, John J Won 1, Rachel L Graham 1, Kenneth H Dinnon 3rd 1, Amy C Sims 1, Joy Y Feng 2, Tomas Cihlar 2, Mark R Denison 3, Ralph S Baric 1, Timothy P Sheahan 4

Affiliations expand

Free PMC article

Abstract

The genetically diverse Orthocoronavirinae (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC50 values. Of known CoVs, the members of the deltacoronavirus genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.

Keywords: Broad-spectrum antivirals; Coronavirus; Emerging viruses; GS-5743; Remdesivir.




84

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Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV.

Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, Montgomery SA, Hogg A, Babusis D, Clarke MO, Spahn JE, Bauer L, Sellers S, Porter D, Feng JY, Cihlar T, Jordan R, Denison MR, Baric RS.

Nat Commun. 2020 Jan 10;11(1):222. doi: 10.1038/s41467-019-13940-6.

PMID: 31924756 Free PMC article.

85

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Characterization of Ebola Virus Disease (EVD) in Rhesus Monkeys for Development of EVD Therapeutics.

Warren T, Zumbrun E, Weidner JM, Gomba L, Rossi F, Bannister R, Tarrant J, Reed M, Lee E, Raymond JL, Wells J, Shamblin J, Wetzel K, Donnelly G, Van Tongeren S, Lackemeyer N, Steffens J, Kimmel A, Garvey C, Bloomfield H, Blair C, Singh B, Bavari S, Cihlar T, Porter D.

Viruses. 2020 Jan 13;12(1):92. doi: 10.3390/v12010092.

PMID: 31941095 Free PMC article.

86

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Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection.

de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H.

Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6771-6776. doi: 10.1073/pnas.1922083117. Epub 2020 Feb 13.

PMID: 32054787 Free PMC article.

87

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Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2.

Williamson BN, Feldmann F, Schwarz B, Meade-White K, Porter DP, Schulz J, van Doremalen N, Leighton I, Kwe Yinda C, Pérez-Pérez L, Okumura A, Lovaglio J, Hanley PW, Saturday G, Bosio CM, Anzick S, Barbian K, Cihlar T, Martens C, Scott DP, Munster VJ, de Wit E.

bioRxiv. 2020 Apr 22:2020.04.15.043166. doi: 10.1101/2020.04.15.043166. Preprint.

PMID: 32511319 Free PMC article. Updated.

88

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Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice.

Pruijssers AJ, George AS, Schäfer A, Leist SR, Gralinksi LE, Dinnon KH, Yount BL, Agostini ML, Stevens LJ, Chappell JD, Lu X, Hughes TM, Gully K, Martinez DR, Brown AJ, Graham RL, Perry JK, Du Pont V, Pitts J, Ma B, Babusis D, Murakami E, Feng JY, Bilello JP, Porter DP, Cihlar T, Baric RS, Denison MR, Sheahan TP.

bioRxiv. 2020 Apr 27:2020.04.27.064279. doi: 10.1101/2020.04.27.064279. Preprint.

PMID: 32511392 Free PMC article. Updated.

89

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A nanoluciferase SARS-CoV-2 for rapid neutralization testing and screening of anti-infective drugs for COVID-19.

Xie X, Muruato AE, Zhang X, Lokugamage KG, Fontes-Garfias CR, Zou J, Liu J, Ren P, Balakrishnan M, Cihlar T, Tseng CK, Makino S, Menachery VD, Bilello JP, Shi PY.

bioRxiv. 2020 Jun 23:2020.06.22.165712. doi: 10.1101/2020.06.22.165712. Preprint.

PMID: 32607511 Free PMC article. Updated.




https://pubmed.ncbi.nlm.nih.gov/32479636/


Cite Share

Remdesivir (GS-5734) Is Efficacious in Cynomolgus Macaques Infected With Marburg Virus.

Porter DP, Weidner JM, Gomba L, Bannister R, Blair C, Jordan R, Wells J, Wetzel K, Garza N, Van Tongeren S, Donnelly G, Steffens J, Moreau A, Bearss J, Lee E, Bavari S, Cihlar T, Warren TK.

J Infect Dis. 2020 Nov 9;222(11):1894-1901. doi: 10.1093/infdis/jiaa290.

PMID: 32479636