Review
An update review of emerging small-molecule therapeutic options for COVID-19

https://doi.org/10.1016/j.biopha.2021.111313Get rights and content
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Highlights

  • The present review showcases the major pharmaceutical drug targets that can be used to fight against the SARS-CoV-2 pandemic.

  • Nonstructural protein inhibitors are essential in preventing host cell entry of coronaviruses and are thoroughly discussed.

  • Potential SARS-CoV-2 drug targets, including their structures, effects and potential impacts, are reviewed.

  • Small-molecule therapeutics and their modes of disease suppression are explained in detail.

Abstract

The SARS-CoV-2 outbreak and pandemic that began near the end of 2019 has posed a challenge to global health. At present, many candidate small-molecule therapeutics have been developed that can inhibit both the infection and replication of SARS-CoV-2 and even potentially relieve cytokine storms and other related complications. Meanwhile, host-targeted drugs that inhibit cellular transmembrane serine protease (TMPRSS2) can prevent SARS-CoV-2 from entering cells, and its combination with chloroquine and dihydroorotate dehydrogenase (DHODH) inhibitors can limit the spread of SARS-CoV-2 and reduce the morbidity and mortality of patients with COVID-19. The present article provides an overview of these small-molecule therapeutics based on insights from medicinal chemistry research and focuses on RNA-dependent RNA polymerase (RdRp) inhibitors, such as the nucleoside analogues remdesivir, favipiravir and ribavirin. This review also covers inhibitors of 3C-like protease (3CLpro), papain-like protease (PLpro) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.

Abbreviations

3CLpro
3C-Like protease
6MP
6-Mercaptopurine
6TG
6-Thioguanine
ACE2
Angiotensin-converting enzyme 2
AMPK
AMP-activated protein kinase
BECN1
Beclin1
BSAs
Broad-spectrum antiviral drugs
CoV
Coronavirus
COVID-19
2019 Coronavirus disease
CQ
Chloroquine
CMK
Decanoyl-RVKR-chloromethylketone
CPE
Cytopathic effect
DAAs
Direct-acting antiviral agents
DHO
Dihydroorotate
DHODH
Dihydroorotate dehydrogenase
E
Envelope protein
EBOV
Ebola virus
ELs
Endolysosomes
EUA
Emergency use authorization
FDA
US Food and Drug Administration
GM1
Monosialotetrahexosylganglioside 1
GTP
Guanosine triphosphate
HA
Haemagglutinin
HC
QHydroxychloroquine
HIV
Human immunodeficiency virus
HTAs
Host-targeting antivirals
HyCoSuL
Hybrid Combinatorial Substrate Library
IMPDH
Inosine monophosphate dehydrogenase
IFN
Interferon
IRF3
Interferon regulatory factor 3
LPV/r
Lopinavir/ritonavir
M
Membrane protein
MERS-CoV
Middle East respiratory syndrome coronavirus
Mpro
Main protease
N
Nucleocapsid protein
NIAID
National Institute of Allergy and Infectious Diseases
nsps
Non-structural proteins
PC
Pro-protein convertase
PIP2
Phosphatidylinositol 4,5-bisphosphate
PLpro
Papain-like protease
PP2A
Protein phosphatase 2A
RBV
Ribavirin
RDP
Ribavirin diphosphate
RdRp
RNA-dependent RNA polymerase
RMP
Ribavirin monophosphate
RTP
Ribavirin triphosphate
S
Spike protein
SAR
Structure-activity relationship
SARS-CoV
Severe acute respiratory syndrome coronavirus
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SKP2
S-Phase kinase-associated protein 2
TGN
Trans-Golgi network
WHO
World Health Organization

Keywords

Coronaviruses
SARS-CoV-2
RNA-dependent RNA polymerase (RdRp)
3C-like protease (3CLpro)
Papain-like protease (PLpro)
Transmembrane serine protease (TMPRSS2)

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