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Molnupiravir, an orally available antiviral drug, is a mutagen of SARS-CoV-2.35,36,37 According to research reported by Kabinger et al., the active form of molnupiravir, beta-D-N4-hydroxycytidine triphosphate, can be directly incorporated into RNA as a substrate instead of cytidine triphosphate or uridine triphosphate, leading to mutated RNA products.38 Structural analysis of RdRp-mutated RNA indicated that beta-D-N4-hydroxycytidine triphosphate formed a stable base pair with G or A in the RdRp active region, thus escaping proofreading and synthesizing mutated RNA. Like molnupiravir, ribavirin abrogates viral RNA synthesis by incorporation into nascent RNA strands.39,40,41,42 Cheung et al. confirmed it is a mutagen for influenza virus by increasing the G-to-A and C-to-T mutation rates in vitro.39 The molecular docking study of Bylehn et al. indicated that it binds strongly at the active site of SARS-CoV-2 RdRp.43 However, their results revealed that ribavirin does not bind the nucleotide on the complementary strand as effectively and seems to act by a different mechanism.
The structure of TMPRSS2 is characterized by an N-terminal cytoplasmic domain, a transmembrane domain, a class A LDL receptor domain, a scavenger receptor cysteine-rich domain, and an activation domain linked to a serine protease domain via a disulfide bond.54,159,170 Since no crystal structure of TMPRSS2 is available, repurposing or optimizing inhibitors against well-known serine proteases may facilitate the discovery of effective TMPRSS2 inhibitors against SARS-CoV-2.170,171,172 For example, Sun et al. identified structurally similar serine proteases using a structure-based phylogenetic computational tool to find potential inhibitors of TMPRSS2.173 According to their computational results, six serine peptidases, including kallikrein-related B1, had a high structural similarity to the TMPRSS2 S1 protease domain. The kallikrein-related B1 inhibitor avoralstat with high potential to be repurposed for COVID-19 therapy was identified. In addition, based on a previously designed peptidomimetic tetrapeptide with inhibitory activity against matriptase, Shapira et al. developed a small library of peptidomimetic compounds to screen for inhibitors of TMPRSS2.174 Through the screening process, they found that N-0385, containing a ketobenzothiazole warhead, inhibits TMPRSS2. Then, by building a homology model of TMPRSS2 using the crystal structure of matriptase, they found that the catalytic Ser-441 residue of the enzyme forms a covalent bond with the warhead of N-0385. This contributes to its inhibitory activity against TMPRSS2. Rational structure-based drug design was also applied to discover TMPRSS2 inhibitors by Mahoney et al..175 Based on molecular docking studies using a published homology model of TMPRSS2 and substrate specificity data from PS-SCL, a set of ketobenzothiazole inhibitors of HGF-activating serine proteases (including HGF activator [HGFA], matriptase, and hepsin) were developed. After further optimization, they identified multiple potent inhibitors of TMPRSS2. Four of these analogs displayed activity at subnanomolar concentrations, both in the enzyme assay and in blocking the entry of VSV-SARS-CoV-2 chimeras into human Clau-3 epithelial lung cells. Besides blocking the cleavage function of TMPRSS2, molecules with the ability to reduce TMPRSS2 expression on host cells also drew attention for anti-COVID-19 research. A high-throughput screening using a library of 2560 FDA-approved or currently investigated clinical compounds was carried out by Chen et al. to identify small molecules that reduce TMPRSS2 expression.176 They found that halofuginone modulates TMPRSS2 levels through proteasomal-mediated degradation that involves the E3 ubiquitin ligase component DDB1- and CUL4-associated factor 1.
Derivatives of amino acids are amides with broad medicinal values and development prospects. They were also widely investigated in recent COVID-19 research, especially as inhibitors of Mpro. Paxlovid is a co-packaged combination of nirmatrelvir and ritonavir.517,518 It is necessary to indicate that both compounds are derivatives of amino acids. Nirmatrelvir is a derivative of proline. It is an orally bioactive inhibitor of SARS-CoV-2 Mpro .519 Ritonavir is an L-valine derivative that has been applied as an HIV-1 protease inhibitor and as a cytochrome P450 (CYP3A) inhibitor.520 Ritonavir does not directly act on SARS-CoV-2 but is used to inhibit CYP3A-mediated metabolism of nirmatrelvir, resulting in increased plasma concentrations of nirmatrelvir.41 Owen et al. first developed Nirmatrelvir by optimizing PF-00835231, a potent inhibitor of SARS-CoV Mpro.84 According to their study, niramatrelvir exhibited good selectivity, safety, and protection against infection in a mouse-adapted SARS-CoV-2 model. Moreover, the results from a phase I single ascending dose study in healthy adult participants proved that nirmatrelvir was safe and well tolerated and exhibited a significant boost in plasma concentrations when co-administered with ritonavir.521 As Mpro is a highly conserved target protein, the antiviral potency of nirmatrelvir does not decrease when treating Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) SARS-CoV-2 variants.522 However, recent preprints have reported that SARS-CoV-2 gains nirmatrelvir resistance after treatment with nirmatrelvir after in vitro culturing.523,524 There is also evidence that nirmatrelvir-resistant mutations have been acquired by the SARS-CoV-2 virus circulating in people.525,526,527 Boceprevir belongs to the imino acids and has potential activity against HCV genotype 1. Ma et al. first identified its anti-SARS-CoV-2 activity as an Mpro inhibitor and proved its in vitro activity.96 This anti-SARS-CoV-2 mechanism and effect was also proved by Fu et al. and Qiao et al..79,95 Based on the structure of boceprevir and another peptidomimetic compound, the HCV inhibitor telaprevir, Qiao et al. developed 32 new bicycloproline-containing Mpro inhibitors. As a result, two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays, and significantly reduced lung viral loads and lung lesions in a transgenic mouse model of SARS-CoV-2 infection.79 Kneller et al. developed three hybrid peptidomimetic inhibitors, BBH-1, BBH-2, and NBH-2, by splicing components of boceprevir and narlaprevir, and proved their antiviral properties in vitro relative to nirmatrelvir.86 A study conducted by Xia et al. also showed the in vitro broad-spectrum coronavirus antiviral effect of two rationally designed inhibitors based on the peptidomimetic compounds GC-376, telaprevir, and boceprevir.528 To date, the development of peptidomimetics is the most used strategy in the search of anti-COVID-19 drugs.529 Other peptidomimetics, such as talaprevir, MG-132, and MDL-28170, were