Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China

Abstract

The ongoing COVID-19 pandemic has resulted in millions of deaths globally, highlighting the need to develop potent prophylactic and therapeutic strategies against SARS-CoV-2. Small molecule inhibitors (remdesivir, Paxlovid, and molnupiravir) are essential complements to vaccines and play important roles in clinical treatment of SARS-CoV-2. Many advances have been made in development of anti-SARS-CoV-2 inhibitors in China, but progress in discovery and characterization of pharmacological activity, antiviral mechanisms, and clinical efficacy are limited. We review development of small molecule anti-SARS-CoV-2 drugs (azvudine [approved by the NMPA of China on July 25, 2022], VV116 [approved by the NMPA of China on January 29, 2023], FB2001, WPV01, pentarlandir, and cepharanthine) in China and summarize their pharmacological activity, potential mechanisms of action, clinical trials and use, and important milestones in their discovery. The role of structural biology in drug development is also reviewed. Future studies should focus on development of diverse second-generation inhibitors with excellent oral bioavailability, superior plasma half-life, increased antiviral activity against SARS-CoV-2 and its variants, high target specificity, minimal side effects, reduced drug-drug interactions, and improved lung histopathology.

Keywords: Azvudine; COVID‐19; Cepharanthine; FB2001; SARS‐CoV‐2; VV116.

Graphical abstract

Fig. 1

Chemical structures of representative SARS-CoV-2 inhibitors. Azvudine, a self-developed oral SARS-CoV-2 RdRp inhibitor, approved by the NMPA of China; VV116, the first deuterated oral RdRp candidate, approved by the NMPA of China; FB2001, China's first inhaled M^pro clinical candidate; WPV01, non-covalent M^pro inhibitor; Proxalutamide, ACE2 inhibitor, approved for emergency use in Uruguay; Cepharanthine, natural product-derived ACE2 inhibitor.

Fig. 2

SARS-CoV-2 genome structure and structural biology advances. (a) Genome-wide structure and function modeling of SARS-CoV-2 (https://seq2fun.dcmb.med.umich.edu/COVID-19/). (b) Timeline of structural biology studies on SARS-CoV-2 in China over the last three years. (c) The molecular architecture of SARS-CoV-2. Reproduced with permission. Copyright 2020, Elsevier Inc. (d) Novel mechanism of SARS-CoV-2 RNA capping. Reproduced with permission. Copyright 2022, Elsevier Inc.

Fig. 3

Discovery of the orally available SARS-CoV-2 RdRp covalent inhibitor azvudine. (a) Important milestones in azvudine discovery from NM-107 to the first-in-class HIV and SARS-CoV-2 dual inhibitor azvudine. (b) Medicinal chemistry efforts led to discovery of the oral RdRp inhibitor azvudine. (c) Proposed mechanism of action of the prodrug azvudine against SARS-CoV-2. (d) Metabolic pathway of azvudine. (e) Structure of SARS-CoV-2 RNA with a cytosine subunit. (f) A diagram showing the SARS-CoV-2 RNA replication process blocked by the active metabolite azvudine triphosphate through formation of a covalent bond.

Fig. 4

Discovery of the first up-and-coming deuterated oral SARS-CoV-2 RdRp covalent candidate VV116. (a) Medicinal chemistry efforts led to discovery of the first deuterated oral RdRp candidate, VV116. (b) Important milestones in VV116 discovery from natural nucleosides to VV116. (c) Proposed mechanism of action of the tri-isobutyrate ester prodrug VV116 against SARS-CoV-2. SARS-CoV-2 RNA replication was blocked by the active metabolite VV116-NMP through formation of a covalent bond.

Fig. 5

Representative SARS-CoV-2 M^pro(3CL^pro) inhibitors and China's first inhaled aerosolized SARS-CoV-2 M^proclinical candidate FB2001. (a) Chemical structures of selected SARS-CoV-2 M^pro inhibitors (PF-07321332, PF-00835231, GC-376, MPI8, 2a, Jun9–62-2R, 23R, and 26 from USA; 15h from Canada; 13b from Germany; QUB-00006-Int-07 from France; YH-6 and S-217622 from Japan; 19 from Sweden; GC-14, LY1, WU-04, 18p, FB2001, MI-23, and Y180 from China) for COVID-19 treatment. (b) The design strategy of FB2001 through analysis of the substrate-binding pocket of SARS-CoV M^pro to guide design of SARS-CoV-2 M^pro inhibitors (based on the high degree of structural homology and similar substrate specificity of M^pro between SARS-CoV-2 and SARS-CoV). (c) Broad-spectrum activity of FB2001 against SARS-CoV-2 and variants, and comparison of activity between FB2001 with US FDA-approved PF-07321332. (d) Synergistic analysis of the combination of FB2001 and remdesivir. In cases where the synergy score <−10 the interaction was likely to be antagonistic, −10 < synergy score <10 indicated an additive effect, and synergy score >10 indicate a synergistic effect. (e) Schematic representation of the inhibitory mechanism of FB2001. The aldehyde carbon of FB2001 reacts reversibly with the nucleophilic sulfur atom of Cys145, thus forming a covalently bound tetrahedral complex. (f) The structure of SARS-CoV-2 M^pro in complex with FB2001. Cartoon representation of M^pro in complex with FB2001 in two different views. The catalytic dyad (His41 and Cys145) is indicated as green and red spheres, respectively. FB2001 is shown as magenta sticks. Reproduced with permission. Copyright 2022, Elsevier B.V.

Fig. 6

Selected bioactive natural products in COVID-19 therapy and clinical candidate cepharanthine. (a) Chemical structures of selected SARS-CoV-2 inhibitors (Ursodeoxycholic acid, initial study from UK; Gallinamide A, initial study from Australia; Plitidepsin, initial study from USA; Bafilomycin B₂ and Cepharanthine, initial studies from China) for COVID-19 treatment. (b) Important milestones in progress cepharanthine inhibition of SARS-CoV-2. This timeline shows the speed with which drugs can be developed with collaboration.

Fig. 7

Chemical structures of Pentarlandir™ UPPTA.