Graphical 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 (3CL pro ), papain-like protease (PL pro ) and other potentially innovative active ingredient molecules, describing their potential targets, activities, clinical status and side effects.
【저자키워드】 SARS-CoV-2, Coronaviruses, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, HIV, Human immunodeficiency virus, ACE2, angiotensin-converting enzyme 2, RNA-dependent RNA polymerase (RdRp), SARS-CoV, severe acute respiratory syndrome coronavirus, MERS-CoV, Middle East respiratory syndrome coronavirus, CPE, cytopathic effect, RdRp, RNA-dependent RNA polymerase, FDA, US Food and Drug Administration, IFN, interferon, WHO, World Health Organization, CoV, coronavirus, CQ, Chloroquine, Mpro, main protease, EUA, Emergency Use Authorization, papain-like protease (PLpro), S, spike protein, COVID-19, 2019 coronavirus disease, N, nucleocapsid protein, DHODH, dihydroorotate dehydrogenase, AMPK, AMP-activated protein kinase, IRF3, interferon regulatory factor 3, M, Membrane protein, E, Envelope protein, TGN, Trans-Golgi Network, PC, Pro-protein Convertase, EBOV, Ebola virus, 3CLpro, 3C-Like protease, 6MP, 6-Mercaptopurine, 6TG, 6-Thioguanine, BECN1, Beclin1, BSAs, Broad-spectrum antiviral drugs, CMK, Decanoyl-RVKR-chloromethylketone, DAAs, Direct-acting antiviral agents, DHO, Dihydroorotate, ELs, Endolysosomes, GM1, Monosialotetrahexosylganglioside 1, GTP, Guanosine triphosphate, HA, Haemagglutinin, HC, QHydroxychloroquine, HTAs, Host-targeting antivirals, HyCoSuL, Hybrid Combinatorial Substrate Library, IMPDH, Inosine monophosphate dehydrogenase, LPV/r, Lopinavir/ritonavir, NIAID, National Institute of Allergy and Infectious Diseases, nsps, Non-structural proteins, PIP2, Phosphatidylinositol 4,5-bisphosphate, PLpro, Papain-like protease, PP2A, Protein phosphatase 2A, RBV, Ribavirin, RDP, Ribavirin diphosphate, RMP, Ribavirin monophosphate, RTP, Ribavirin triphosphate, SAR, Structure-activity relationship, SKP2, S-Phase kinase-associated protein 2, 3C-like protease (3CLpro), Transmembrane serine protease (TMPRSS2),