SARS-CoV-2 gRNA:RTC:RNA primer binds RTC inhibitors

Stable Identifier
R-HSA-9694541
Type
Reaction [binding]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
double membrane vesicle viral factory outer membrane
ReviewStatus
5/5
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SARS-CoV-2 gRNA:RTC:RNA primer binds RTC inhibitors
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Remdesivir (GS-5734) is an investigational nucleotide analogue drug that was developed for its broad spectrum antiviral potential against Ebola and Marburg virus activity (Siegel et al. 2017). It targets and inhibits viral RNA-dependent RNA polymerase (nsp12, RdRP), the key component of the replication transcription complex (RTC) (Agostini et al. 2018, Brown et al. 2019, Gordon et al. 2020). Remdesivir is being investigated for potential antiviral activity against SARS-CoV-2 by targeting viral replication (Agostini et al. 2018). Gordon et al. demonstrate remdesivir possesses broad antiviral activity against RNA viruses, including SARS-CoV, MERS-CoV and SARS-CoV-2 in-vitro (Gordon et al. 2020b). It could prevent asymptomatic, mild or moderate COVID-19 cases from progressing to severe disease (clinical trials NCT04252664, NCT04257656) but results so far in infected people have been mixed.

EIDD-2801, is an isopropylester prodrug of the ribonucleoside analogue N4-hydroxycytidine (NHC, EIDD-1931) that shows broad spectrum antiviral activity against various RNA viruses including Ebola, Influenza and CoV (Toots et al. 2019). NHC acts as a competitive alternative substrate for virally encoded RNA-dependent RNA polymerases. NHC was shown to inhibit multiple genetically-distinct Bat-CoV viruses in human primary epithelial cells without affecting cell viability. Prophylactic/therapeutic oral administration of NHC reduced lung titers and prevented acute lung failure in C57B/6 mice infected with CoV. The potency of NHC against multiple coronaviruses, its therapeutic efficacy, and oral bioavailability in vivo, all highlight its potential as an effective antiviral against SARS-CoV-2 and other future zoonotic coronaviruses (Sheahan et al. 2020). The clinical trial NCT04575584 was terminated prematurely for ethical reasons because molnupiravir reached its endpoint of effectiveness against COVID-19. However, interim WHO Solidarity Trial results showed no benefits in 2,750 people treated with remdesivir (WHO Solidarity Trial Consortium, 2020).

Simeprevir is used in combination with other medications for the treatment of hepatitis C genotype 1 and 4. It not only inhibits SARS-CoV-2 3CLpro and transcription, but also modulates host immune responses. Simeprevir reduces viral load by multiple orders of magnitude and synergizes with remdesivir in Vero E6 and A549-ACE2 cells (Lo et al, 2021).
Literature References
PubMed ID Title Journal Year
32094225 The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Gotte, M, Gordon, CJ, Feng, JY, Tchesnokov, EP, Porter, DP

J. Biol. Chem. 2020
31645453 Characterization of orally efficacious influenza drug with high resistance barrier in ferrets and human airway epithelia

Hart, M, Kolykhalov, AA, Bluemling, GR, Sticher, ZM, Plemper, RK, Painter, GR, Toots, M, Mitchell, DG, Natchus, MG, Cox, RM, Reddy, PG, Shean, RC, Plesker, R, Yoon, JJ, Makhsous, N, Barrena, AH, Greninger, AL

Sci Transl Med 2019
32258351 Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses

Amirian, ES, Levy, JK

One Health 2020
32284326 Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency

Gotte, M, Woolner, E, Gordon, CJ, Feng, JY, Perry, JK, Tchesnokov, EP, Porter, DP

J. Biol. Chem. 2020
32253226 An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice

Harcourt, J, Schäfer, A, Saindane, M, Hill, CS, Sims, AC, Zhou, S, Swanstrom, R, Painter, G, Leist, SR, Thornburg, NJ, Chappell, JD, Pruijssers, AJ, Stevens, LJ, Tamin, A, Hughes, TM, George, AS, Baric, RS, Montgomery, SA, Kolykhalov, AA, Sheahan, TP, Bluemling, GR, Brown, AJ, Graham, RL, Natchus, MG, Dinnon, KH, Agostini, ML, Lu, X, Denison, MR

Sci Transl Med 2020
34075346 Simeprevir Potently Suppresses SARS-CoV-2 Replication and Synergizes with Remdesivir

Canard, B, Wong, KB, Guillemot, JC, Wu, KP, Chen, YW, Ko, H, Dikic, I, Mok, VCT, Liang, PH, Chan, MCW, Cheung, PM, Hui, DSC, Aik, WS, Chan, FKL, Li, Z, Mok, CKP, Wang, K, Huang, J, Kaur, S, Cheung, HH, Chan, AKN, Eydoux, C, Zuo, Z, Shin, D, Ng, WL, Lee, MH, Khan, KS, Lai, HM, Ma, B, Ng, KC, Selisko, B, He, X, Ho, JCW, Lo, HS, Hui, KPY

ACS Cent Sci 2021
31233808 Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase

Sheahan, TP, Cihlar, T, Brown, AJ, Denison, MR, Won, JJ, Graham, RL, Feng, JY, Sims, AC, Dinnon, KH, Baric, RS

Antiviral Res. 2019
29511076 Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease

Andres, EL, Sheahan, TP, Cihlar, T, Smith, EC, Mackman, RL, Graham, RL, Feng, JY, Sims, AC, Siegel, D, Agostini, ML, Lu, X, Denison, MR, Ray, AS, Clarke, MO, Case, JB, Jordan, R, Baric, RS

mBio 2018
Participants
Input
Output
Participates
as an event of
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Jassal, B  (2020-08-06)
Reviewed
Shoichet, BK  (2020-05-14)
Acencio, ML  (2020-09-09)
Created
Cook, J  (2020-07-07)
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