COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus and possesses a positive-sense single-stranded RNA genome that contains 14 open reading frames (ORFs). Two ORFs encode polyproteins PP1a and PP1b. Four ORFs encode a series of structural proteins, including the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins. In the SARS-CoV-2 lifecycle, the S protein, which recognizes the human ACE2 receptor and is cleaved by host proteases, is responsible for virus binding and entry into host cells. Subsequently, Mpro and PLpro are necessary for the production and function of non-structural proteins (NSPs).
The key NSP RNA-dependent RNA polymerase (RdRp, also known as NSP12) catalyzes the synthesis of viral RNA and plays a central role in the lifecycle of SARS-CoV-2. Therefore, targeting these functional proteins is a rational strategy to inhibit infection and the replication of SARS-CoV-2.
Small molecules targeting specific signals and functions are widely applied in the treatment of diseases. Compared with biologics such as monoclonal antibodies and plasma products, small molecules are more flexible in binding with target molecules when acting as antagonist or agonist. Their lower production cost and higher stability also make them ideal therapeutic agents for both clinical and research applications. In parallel with the growing understanding of the pathogenic mechanisms of SARS-CoV-2 infection, small molecules from natural sources or those produced via chemical synthesis have demonstrated their immense therapeutic potential by intervening with various processes. The development of small molecules to treat COVID-19 has been achieved by several strategies, including computer-aided lead compound design and screening, natural product discovery, drug repurposing, and combination therapy.
According to incomplete statistics, so far, 10 small-molecule COVID-19 therapeutic drugs have been approved or authorized globally.
- Favipiravir, an effective and selective RNA-dependent RNA polymerase inhibitor, is applied to treat influenza virus infections.
- Remdesivir is a nucleotide prodrug of an adenosine analog. It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication by terminating RNA transcription prematurely. Remdesivir has demonstrated in vitro and in vivo activity against SARS-CoV-2.
- 2-Deoxy-D-glucose, an analog of glucose, is a glycolytic inhibitor with antiviral.
- Proxalutamide is a potent second-generation non-steroidal androgen receptor (AR) antagonist.
- Molnupiravir, the oral prodrug of beta-D-N4-hydroxycytidine (NHC), is a ribonucleoside that has shown antiviral activity against SARS-CoV-2 in vitro and in clinical trials.
- Nirmatrelvir/Ritonavir is currently being studied for the treatment of coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus.
- Baricitinib is a selective inhibitor of JAK 1 and 2 and blocks the intracellular signaling pathway of inflammatory cytokines, including interleukin-2, interleukin-6, interleukin-10, interferon-γ, and granulocyte-macrophage colony-stimulating factor.
- VV116 is an oral drug candidate of nucleoside analog against SARS-CoV-2.
- Azvudine is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp).
- Ensitrelvir is an orally bioavailable small molecule with in vitro activity against a wide variety of SARS-CoV-2 variants and subvariants.
| Agent | Structure | Mechanism of action | Structure category |
| Favipiravir |  | RdRp inhibitor | Nucleoside/Nucleoside analog |
| Remdesivir |  | RdRp inhibitor | Nucleoside/Nucleoside analog |
| 2-Deoxy-D-glucose |  | Glycolytic inhibitor | Glucose analog |
| Proxalutamide |  | Androgen receptor antagonist | Azoles |
| Molnupiravir |  | RdRp inhibitor | Nucleoside/Nucleoside analog |
| Nirmatrelvir/Ritonavir |   | CYP3A inhibitor/Protease inhibitor | Amides |
| Baricitinib |  | JAK 1 and 2 inhibitor | Nucleoside/Nucleoside analog |
| VV116 |  | RdRp inhibitor | Nucleoside/Nucleoside analog |
| Azvudine |  | RdRp inhibitor | Nucleoside/Nucleoside analog |
| Ensitrelvir |  | 3C-like protease inhibitor | Nucleoside/Nucleoside analog |
Reference
Lei S, Chen X, Wu J, Duan X, Men K. Small molecules in the treatment of COVID-19. Signal Transduct Target Ther. 2022 Dec 5;7(1):387. DOI: 10.1038/s41392-022-01249-8. PMID: 36464706; PMCID: PMC9719906.