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Remdesivir and COVID-19

As of May 04, 2002, according to the John Hopkins University, more than 3.5 million people have tested positive for the coronavirus worldwide, and over 248,000 people have died. Therefore, effective therapeutic drugs for coronavirus disease 2020 (COVID-19) are desperately needed for the control of the current pandemic.

A recent
clinical trial at the NIH now shows that Remsdesivir accelerates recovery from advanced COVID-19. Apparently, according to the latest report, patients treated with Remdesivir recover more quickly in comparison to untreated ones. There is hope.  It is hoped that this treatment helps COVID-19 patients recover with minimal side effects. However, only time will tell how effective Remdesivir is as a treatment of COVID-19.


Figure 1: Remdesivir. (Left) Chemical structure of Remdesivir, or GS 5734. Formula: C27H35N6O8P; 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate; l-alanine, N-((S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-d-altrononitrile. Molecular weight: Average: 602.585; Monoisotopic: 602.225399109.  (Right) Partial structure derived from the structure PDB ID 7BV2. https://pubchem.ncbi.nlm.nih.gov/compound/Remdesivir


Remdesivir, GS-5734, is an antiviral drug developed by Gilead Sciences. Remdesivir is an adenosine triphosphate analog. In 2016 Warren et al. investigated the drug for the treatment of Ebola, and Sheahan et al., in 2017, demonstrated the drug is also active in coronaviruses. A more recent test investigated Remdesivir as a potential drug for the treatment of patients infected with SARS-CoV-2, the coronavirus responsible for COVID-19 (de Wit et al.; Ledford). More recently, in May 2020, the FDA authorized the antiviral drug Remdesivir for the emergency treatment of hospitalized patients with coronavirus infections, as told by the President of the United States of America on Friday, May 01, 2020.

The viral RNA-dependent RNA polymerase (RdRp) is needed for replication of SARS-CoV-2 viral RNA. RdRp is the likely target of the investigational nucleotide analogue Remdesivir. Agostini et al., in 2018, suggested that the Remdesivir nucleoside analog inhibits the viral RNA polymerase. Recently, Gao et al. reported the structure of the COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-Å resolution solved by cryo-EM. The structure revealed the presence of the conserved architecture of the polymerase core of the viral polymerase protein family. The non-structural protein nsp12 was found to contain a newly identified β-hairpin domain at its N-terminus. The structural model shows how Remdesivir binds to the polymerase. The structure provides a guiding principle for the design of new antiviral therapeutics targeting viral RdRp.


Figure 2: Complex of nsp12-nsp7-nsp8 bound to the template-primer RNA and triphosphate form of Remdesivir. Cryo EM structure PDB ID 7BV2.  https://www.rcsb.org/structure/7BV2.

The nonstructural protein nsp7 produced by both pp1a and pp1ab forms a hexadecameric complex with nsp8 and is thought to act as a processivity clamp for RNA polymerase. The RNA-dependent RNA polymerase (RdRp), nsp12, is produced by pp1ab only.  

 



Figure 3: Remdesivir-RNA primer. Extracted from source PDB ID 7BV2. (Left) Stick model with Remdesivir shown as spheres. (Right) Surface model of the RNA with Remdesivir shown as sticks.

Incorporation of the analog into viral RNA prevents the addition of nucleotides leading to the termination of RNA transcription preventing the virus from multiplying. Enzyme kinetic studies performed by Gordon et al., in 2020, indicate that this RdRp efficiently incorporates the active triphosphate form of Remdesivir into RNA. Incorporation of the Remdesivir triphosphate at position i caused termination of RNA synthesis at position i+3. Almost identical results were found for SARS-CoV, MERS-CoV, and SARS-CoV-2 RdRps. A delayed chain-termination is Remdesivir’s plausible mechanism of action. Also, Remdesivir shows broad-spectrum antiviral activity against several RNA viruses, including Ebola virus (EBOV) and Middle East respiratory syndrome coronavirus (MERS-CoV). 


Reference

John Hopkins University coronavirus info:  https://coronavirus.jhu.edu/map.html

Remsdesivir trial:
https://www.cnn.com/2020/04/16/health/coronavirus-remdesivir-trial/index.html.

Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R, Ray AS, Cihlar T, Siegel D, Mackman RL, Clarke MO, Baric RS, Denison MR: Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018 Mar 6;9(2). pii: mBio.00221-18. doi: 10.1128/mBio.00221-18. [PubMed]

de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, Scott D, Cihlar T, Feldmann H: Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020 Feb 13. pii: 1922083117. doi: 10.1073/pnas.1922083117. [PNAS]

Ledford H: Hopes rise on coronavirus drug remdesivir. Nature. 2020 Apr 29. pii: [PubMed]

Calvin J. Gordon, Egor P. Tchesnokov, Emma Woolner, Jason K. Perry, Joy Y. Feng, Danielle P. Porter, and Matthias Götte; Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. JBC April 13, 2020. [JBC]

Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, Siegel D, Perron M, Bannister R, Hui HC, Larson N, Strickley R, Wells J, Stuthman KS, Van Tongeren SA, Garza NL, Donnelly G, Shurtleff AC, Retterer CJ, Gharaibeh D, Zamani R, Kenny T, Eaton BP, Grimes E, Welch LS, Gomba L, Wilhelmsen CL, Nichols DK, Nuss JE, Nagle ER, Kugelman JR, Palacios G, Doerffler E, Neville S, Carra E, Clarke MO, Zhang L, Lew W, Ross B, Wang Q, Chun K, Wolfe L, Babusis D, Park Y, Stray KM, Trancheva I, Feng JY, Barauskas O, Xu Y, Wong P, Braun MR, Flint M, McMullan LK, Chen SS, Fearns R, Swaminathan S, Mayers DL, Spiropoulou CF, Lee WA, Nichol ST, Cihlar T, Bavari S: Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2. [PMC]

Bio-Synthesis Inc. is pleased to offer a large variety of oligonucleotides and peptides, modified or unmodified, for a number of research applications, including COVID 19 testing, analysis and vaccine development!

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