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SARS-CoV-2 Antiviral Therapy - PubMed

Review

. 2021 Dec 15;34(4):e0010921.

doi: 10.1128/CMR.00109-21. Epub 2021 Jul 28.

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Review

SARS-CoV-2 Antiviral Therapy

Kaiming Tao et al. Clin Microbiol Rev. .

Abstract

The development of effective antiviral therapy for COVID-19 is critical for those awaiting vaccination, as well as for those who do not respond robustly to vaccination. This review summarizes 1 year of progress in the race to develop antiviral therapies for COVID-19, including research spanning preclinical and clinical drug development efforts, with an emphasis on antiviral compounds that are in clinical development or that are high priorities for clinical development. The review is divided into sections on compounds that inhibit SARS-CoV-2 enzymes, including its polymerase and proteases; compounds that inhibit virus entry, including monoclonal antibodies; interferons; and repurposed drugs that inhibit host processes required for SARS-CoV-2 replication. The review concludes with a summary of the lessons to be learned from SARS-CoV-2 drug development efforts and the challenges to continued progress.

Keywords: SARS-CoV-2; antiviral therapy; drug repurposing; monoclonal antibody; nucleoside analogs.

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Figures

FIG 1
FIG 1

RNA-dependent RNA polymerase (RdRp) inhibition. (A) Coronavirus RdRp enzymes catalyze genome copying and the transcription of multiple subgenomic RNAs. The RdRp-associated replication-transcription complex contains two accessory proteins (nsp7 and nsp8) and an exonuclease (not shown). (B) Remdesivir is a prodrug of GS-441524 which inhibits RdRp by causing delayed chain termination. (C) Molnupiravir is a prodrug of N-hydroxycytidine, which causes lethal viral mutagenesis.

FIG 2
FIG 2

The SARS-CoV-2 Main protease (Mpro) enzyme is responsible for cleaving the polyprotein 1a/b at 11 sites. Mpro is a homodimer that is the target of multiple drug development efforts. PF-00835231 and GC-376 are two peptidomimetic SARS-CoV-2 Mpro inhibitors.

FIG 3
FIG 3

(A) MAbs function by directly binding to the SARS-CoV-2 spike protein to block binding to the human ACE2 receptor (neutralization) and by recruiting immune effector cells. (B) Most naturally arising SARS-CoV-2 spike antibodies and most MAbs target the receptor binding domain (RBD) while several target the N-terminal domain (NTD). (C) The MAb Fab domains are responsible for antigenic recognition whereas the Fc domains are responsible for immune effector functions. Fc-dependent recruitment of immune effector cells, including Ab-dependent cytotoxicity (ADCC) and Ab-dependent cellular phagocytosis (ADCP) may be particularly important for MAb actions against infected cells. The structures showing the RBD- and NTD-binding MAbs were obtained from entries

7K8T

and

7C2L

, respectively, and rendered using PyMOL.

FIG 4
FIG 4

Four mechanisms by which repurposed drugs target cellular host pathways. (A) TMPRSS2 inhibitors such as camostat prevent the cleavage at the S2’ site thus inhibiting S2-mediated virus-cell fusion. (B) Dihydroorotate inhibitors reduce the high concentrations of pyrimidines required for virus replication. (C) Plitidepsin is an inhibitor of the eukaryotic translation elongation factor eEF1A required to produce the high concentrations of proteins required for virus replication. (D) Apilimod inhibits PIKfyve, an enzyme involved in endosomal trafficking thereby interfering with the early steps of virus replication following the entry of virus into cells.

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