key: cord-0938229-dws0g6zt
authors: Xiang, Rong; Yu, Zhengsen; Wang, Yang; Wang, Lili; Huo, Shanshan; Li, Yanbai; Liang, Ruiying; Hao, Qinghong; Ying, Tianlei; Gao, Yaning; Yu, Fei; Jiang, Shibo
title: Recent advances in developing small-molecule inhibitors against SARS-CoV-2
date: 2021-07-02
journal: Acta Pharm Sin B
DOI: 10.1016/j.apsb.2021.06.016
sha: d2b5dfe3fdc6a57fdf1b60a8c8ebd6a205bf5dc6
doc_id: 938229
cord_uid: dws0g6zt

The COVID-19 pandemic caused by the novel SARS-CoV-2 virus has caused havoc across the entire world. Even though several COVID-19 vaccines are currently in distribution worldwide, with others in the pipeline, treatment modalities lag behind. Accordingly, researchers have been working hard to understand the nature of the virus, its mutant strains, and the pathogenesis of the disease in order to uncover possible drug targets and effective therapeutic agents. As the research continues, we now know the genome structure, epidemiological and clinical features, and pathogenic mechanism of SARS-CoV-2. Here, we summarized the potential therapeutic targets involved in the life cycle of the virus. On the basis of these targets, small-molecule prophylactic and therapeutic agents have been or are being developed for prevention and treatment of SARS-CoV-2 infection.

shown to bind to ACE2 and SARS-CoV-2 S protein 55,56 . The results of Beddingfield et al. 54 suggest that inhibiting S protein interaction with α5β1 integrin and the interaction between α5β1 integrin and ACE2 using ATN-161 represents a promising approach to treat COVID-19.

Watson et al. 57 (Table 1) .

The SARS-CoV-2 S protein plays a key role in recognizing receptor and mediating virus-cell membrane fusion showing itself to be an efficient mediator of viral entry.

The S protein is not only an important binding site for neutralizing antibodies, but it is also a major target for therapeutic drug development. Yang et al. 58 Table 2 ). By studying the mechanism of action, they found that masitinib, a cancer treatment drug developed as a tyrosine-kinase inhibitor, inhibited the activity of the SARS-CoV-2 3CLpro.

To identify drug candidates for clinical trials, Jin and coworkers 79 initiated multiple strategies that combining structure-assisted drug design, virtual drug screening and HTS could rapidly discover novel lead compounds. This strategy resulted in the development of a FRET assay to test more than 10,000 compounds as inhibitors of 3CLpro. First, they identified a mechanism-based inhibitor, N3, by computer-aided drug design and then determined that N3 bound with 3CLpro of SARS-CoV-2 at a resolution of 2.1 Å (PDB code 7BQY) by measuring the crystal structure of 3CLpro in complex with N3. Finally, they found that seven FDA-approved or clinical drugs (ebselen, disulfiram, TDZD-8, tideglusib, carmofur, shikonin and PX-12) could inhibit 3CLpro using an enzymatic inhibition assay.

However, it should be pointed out that the mechanism of action of six of them (ebselen, disulfiram, tideglusib, carmofur, shikonin and PX-12) remains to be elucidated. Ma et al. 80 proved that these six inhibitors were nonspecific inhibitors of 3CLpro. Among these compounds, ebselen and N3 [ Fig. 5A-1 (19, 20) ] showed the strongest inhibition against SARS-CoV-2 in a plaque-reduction assay with IC 50 s of 4.67 and 16.77 μmol/L, respectively (Table 2) (Table 2) , respectively, whereas MAC-5576 did not.

Recently, four inhibitors targeting the 3CLpro of SARS-CoV-2, namely GC376, boceprevir, and calpain inhibitors II and XII [ Fig. 5A-1 (26, 28-30 can inhibit SARS-CoV-2 infection and replication with IC 50 s of 3.3 and 50.1 μmol/L, respectively, by measuring viral-induced CPE ( Table 2) . Through target-based assay, they found that nelfinavir mesylate and boceprevir showed inhibitory activity against 3CL pro. Also, nelfinavir mesylate was selected to evaluate its anti-infective efficacy in female golden Syrian hamsters. Nelfinavir mesylate showed good antiviral effects in vivo, and the viral load in hamster lungs was significantly reduced. (Table 3 ). In a transgenic mouse model, MI-09 or MI-30 could significantly reduce lung viral load and lung lesions. Also, MI-09 or MI-30 showed good pharmacokinetic properties and safety in rats.

PLpro is the other crucial viral protease spurring the discovery of anti-SARS-CoV-2 drugs, and its crystal structure has recently been resolved (PDB code 6W9C). PLpro is also reported to drive virus evasion of host innate immune defenses by reversing host ubiquitination and ISGylation events 109 . Thus, PLpro inhibitors may not only directly inhibit SARS-CoV-2 replication, but also perform a complementary function by normalizing the body's immune response against virus invasion. Previous studies identified that thiopurine (6-mercaptopurine and 6-thioguanine, antitumor drugs) showed inhibitory activity against SARS-CoV and MERS-CoV PLpro 110 , so repurposing these candidates for treating COVID-19 seems to be a reasonable approach.

Some noncovalent small-molecule inhibitors, rac3j, rac3k and rac5c, against Table 2) . Gao et al. 116 showed that GRL-0617 was effective in inhibiting SARS-CoV-2 PLpro activity with an IC 50 of 2.2 ± 0.3 μmol/L and that its mechanism of action was not limited to occupying the substrate pockets, but rather extended to sealing the entrance to the substrate binding cleft, thereby preventing the binding of the substrate. Another team reported that GRL-0617 showed a promising inhibitory activity against SARS-CoV-2 PLpro in vitro with an IC 50 of 2.1 μmol/L and effective antiviral inhibition of SARS-CoV-2 in cell-based assays. No apparent cytotoxicity of GRL-0617 on Vero E6 cells was observed with concentrations up to 100 μmol/L 117 .

RdRp, a nsp, also known as nsp12, catalyzes the synthesis of viral genome, which plays a central role in coronaviral replication. Thus, it is considered as an excellent drug target for antiviral inhibitors. The Rao group 118 solved a cryo-electron microscopy structure of full-length RdRp in complex with nsp7 and nsp8 at a Table 2) . Both prophylactic and therapeutic administration of EIDD-2801, an orally available EIDD-1931-prodrug, in mice infected with SARS-CoV or MERS-CoV, could improve pulmonary function and reduce virus titer and body weight loss 120 . The mechanism of action of EIDD-2801 is different from that of remdesivir. Remdesivir is a chain terminator 134 , while EIDD-2801 causes mutagenesis in the viral RNA. In addition, EIDD-2801 is active against remdesivir-resistant mutants and has a higher genetic barrier to drug resistance than remdesivir 120 . For VEE and influenza viruses, compound EIDD-2801 inhibited RdRp to exert its antiviral functions, but the mechanism of action against coronaviruses was not well documented 135 .

Helicase, a motor protein, is responsible for separation and/or rearrangement of viral nucleic acid duplexes before transcription or replication 136 In addition, clofazimine was shown to inhibit SARS-CoV-2 replication by interfering with the function of helicase 69 . The biggest challenge in targeting helicase is the relatively low selectivity of helicase inhibitors. Right now, no antiviral targeting helicase has moved beyond preclinical development.

The nsp16, or 2′-O-MTase, is another crucial protein responsible for SARS-CoV (Table 2) 146 .

N protein, usually located inside the virions, is an abundant coronavirus protein that binds with the viral genome to form the ribonucleoprotein. It plays a critical role in viral RNA transcription and replication 147 , making it a potential antiviral drug target.

Recent studies showed that N protein is a multifunctional protein responsible for binding to the viral RNA genome and packing it into a long helical nucleocapsid structure 148 . It is also reported to regulate host-pathogen interaction and induce protective immune responses 149 .

The Medhi group 22 identified two potential hit compounds, ZINC00003118440 and ZINC0000146942, both of which might bind the RNA-binding N-terminal domain of SARS-CoV-2 N protein, which were theophylline and pyrimidone derivatives, respectively. Thereafter, Kang et al. 150 , for the first time, resolved the X-ray crystal structure of SARS-CoV-2 N protein at a resolution of 2.7 Å, revealing the specific surface charge distributions that facilitats the drug discovery specific to ribonucleotide binding domain of SARS-CoV-2 N protein.

Studies have shown that the genome sequence of SARS-CoV-2 is very similar to that of SARS-CoV. Several SARS-CoV-2 proteins with >90% sequence similarity, such as S protein, 3CLpro, PLpro, RdRp and 2′-O-MTase, could be used as drug targets.

Meanwhile, many small molecules have been described as potential drug candidates for treatment of COVID-19, but their targets have not been identified. Some of these small-molecule drugs, are summarized below.

Early in the COVID-19 pandemic, some anti-flu drugs (for example, oseltamivir) were applied to treat COVID-19 patients 151 (Table 2) . Notably, nelfinavir effectively inhibited SARS-CoV-2 replication at a low concentration and exhibited the high SI among of them 152 , Indicated that nelfinavir is a potential drug candidate for the treatment of COVID-19 and should therefore be evaluated in patients with SARS-CoV-2 infection.

Repurposing of approved drugs is a time-saving strategy for drug development. In this way, Touret et al. 146 (Table 2) , which was far from satisfactory compared to other compounds tested at the same time. However, some data indicated that compounds with high IC 50 values may have surprising antiviral activity in vivo 127 . Therefore, it is necessary to detect the antiviral activity of these compounds in vivo.

Based on existing treatments, new SARS-CoV-2 mutations are likely to be resistant to drugs. Therefore, an initial suggestion is to use host-targeting therapeutic approach to reduce the aggressiveness and mortality resulted from SARS-CoV-2 infections.

Many studies have shown that host ACE2 is the specific receptor for SARS-CoV-2 S protein 5, 10 . Inhibitors that block the binding between S protein and ACE2 have been (Table 3) 164, 165 .

An anthraquinone compound, emodin, which derived from genus Rheum and Polygonum, can interfere with the interactions between S protein and ACE2 by competing with ACE2 and inhibiting the 3a ion channel of coronavirus 166, 167 .

Promazine is an anti-psychotic drug that shares a similar structure with emodin and presents comparable inhibitory effect on the replication of SARS-CoV with a similar mechanism of action 167 . Based on the similarity of S protein sequences between SARS-CoV-2 and SARS-CoV, we could conclude that emodin and promazine may inhibit SARS-CoV-2 infection by blocking the binding between S protein and ACE2, and both of them are considered as potential drugs for the treatment of COVID-19 [168] [169] [170] .

Nicotianamine, a unique secondary metabolite in soybean, is a potent inhibitor of ACE2 171 , and it is considered as a potential drug candidate for the treatment of COVID-19 172, 173 . Similarly, flavonoids were also a class of natural products which possess antioxidant, anti-inflammatory and antiviral functions. Lead flavonoids (e.g., hesperidin, naringin, ECGC and quercetin) screened out by molecular docking might serve as cell entry inhibitors by targeting S protein or ACE2 174 .

SARS-CoV-2 attaches to the ACE2 receptors via S protein, which is subsequently cleaved by TMPRSS2, a host serine protease that has been exploited as therapeutic targets. Hoffmann and colleagues demonstrated that the TMPRSS2 inhibitors proved useful in blocking virus entry 10 .

Camostat mesylate [ Fig. 8 (68) ], a TMPRSS2inhibitor in clinical, significantly reduced SARS-CoV-2 pseudovirus entry into Calu-3 cells with an IC 50 of ~1 μmol/L with no cytotoxic effects (CC 50 ＞500 μmol/L, Table 3) (Table 3) 180 .

In addition to TMPRSS2, cathepsin B and cathepsin L, being active in the early and J o u r n a l P r e -p r o o f late endosome, respectively, can also trigger viral S protein cleavage and promote viral fusion 181, 182 .

P9, derived from mouse β-defensin-4, is a peptide that interfere cathepsin L activity, which showed antiviral activity against SARS-CoV, MERS-CoV, and influenza viruses through the inhibition of endosomal acidification thus indirectly interfering cathepsin L activity 183 . The researchers optimized P9 by replacing arginine with the weakly positively charged amino acids (histidine and lysine) to generate P9R, which showed significantly higher potency against SARS-CoV-2 infection than P9, as determined by a plaque reduction assay in Vero E6 cells (0.9 vs.

2.4 μg/mL, Table 1 ). And the CC 50 of P9R was >300 μg/mL in MDCK, Vero E6 and A549 cells 184 . Further, the authors describe an eight-branched derivative, 8P9R, that showed more potent antiviral activity (IC 50 =0.3 μg/mL) in high salt condition (PBS) than that of P9R in Vero E6 cells. The cytotoxicity assay indicated that CC 50 of 8P9R was higher than 200 μg/mL in Vero E6 cells ( Table 1 ). The 8P9R can inhibit the two entry pathways of SARS-CoV-2 in cells including endocytic pathway and TMPRSS2-mediated surface pathway by aggregating viral particles. In addition, 8P9R, or the combination of repurposed drugs, arbidol, chloroquine and camostat could significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice 185 .

Amantadine and chlorpromazine [ Fig. 9 (72, 73) ], which were previously used to abrogate viral entry via clathrin-mediated endocytosis 24,186 , proved to have no prominent antiviral efficacy against SARS-CoV-2 and only a partial inhibition at 100 μmol/L for amantadine in Vero E6 cells (Table 3) (Table 3) (Table 3) . As reported, MDL-28170, a cathepsin B inhibitor, could impairs infection by SARS-CoV and Ebola virus 192, 193 , ONO 5334 is a cathepsin K inhibitor 194 , and VBY-825 acts as a reversible cathepsin protease inhibitor 195 . Apilimod, a specific PIKfyve kinase inhibitor, was shown to be effective in inhibiting virus entry, which is in agreement with the report that PIKfyve is predominately presented in early endosomes and plays an important role in maintaining endomembrane homeostasis 196 . Another study reported that apilimod inhibits infection with authentic SARS-CoV-2 strain 2019-nCoV/USA-WA1/2020 virus in Vero E6 cells with an IC 50 of ∼10 nmol/L (Table 3) (Table 3) .

Omeprazole, a proton pump inhibitor used as an antiulcer agent, has been demonstrated to increase the pH of endosomal/Golgi pathway either by inhibiting ATPase proton pomp, or by buffering the pH. This endosomal pH modification will limit the processing of S protein by endosomal proteases, thereby blocking the entry of viruses mediated by the membrane fusion process 146 .

The 3CLpro calpain inhibitors II/XII are also reported to be active against human cathepsin L 88 . Calpain inhibitors II/XII inhibit the activity of cathepsin L with IC 50 s of 0.41 and 1.62 nmol/L, respectively 88 . One of the advantages of calpain inhibitors II and XII, as dual inhibitors, is their ability to target the viral protease 3CLpro and the human protease cathepsin L, thus showing better drug effects at lower doses. Another advantage is that they can inhibit drug resistance.

Cathepsin B/L are crucial elements of the lysosomal pathway, and disruption of these host cell proteases offers potential for COVID-19 therapies. Smieszek et al. 202 conducted a HTS to identify compounds that could downregulate the expression of cathepsin L/cathepsin B. Amantadine (10 μmol/L) can downregulate the expression of the cathepsin L gene, which appears to further disrupt the lysosomal pathway.

Based on this, researchers believe that amantadine can reduce the viral load in SARS-CoV-2-positive patients and that it may be used as an effective treatment to J o u r n a l P r e -p r o o f reduce virus replication and infectivity, which may lead to better clinical outcomes.

Innate immune response plays roles in combating coronavirus infection, while interferon can enhance the immune responses 25 . In human cells, blockage of the signal pathway required for viral replication is expected to exhibit some antiviral effect.

In patients infected with SARS-CoV-2, histological examination showed a strong cytokine storm and inflammatory response, and with the release of large amounts of interleukin (IL)-6, excessive inflammation and further lung damage resulted 26,203 . Thalidomide [ Fig. 10A (84) ] has anti-inflammatory activity owing to its ability to accelerate the degradation of messenger RNA in blood cells, thereby reducing reduce tumor necrosis factor-α. In addition, thalidomide can increase the secretion of interleukins, such as IL-12, and activate natural killer cells 204 .

Thalidomide was one of many drugs redirected after the COVID-19 outbreak and used in clinical trials to treat COVID-19 patients (Table 3) 205 . It is a treatment for cancer and inflammatory diseases, but it is currently being used in two phase 2 clinical trials in combination with low-dose hormone therapy and adjuvant therapy for COVID-19.

Multiple sclerosis (MS) is an immune-mediated neurological disease that requires long-term immunotherapy and has been shown to increase the risk of SARS-CoV-2 infection 206 . Fingolimod [ Fig. 10A (85) ], a sphingosine-1-phosphate receptor immunomodulator, which is effective in the treatment of MS and is currently being tested as a treatment for COVID-19-associated acute respiratory distress syndrome (Table 3) 205, 207 . A patient with MS infected with SARS-CoV-2 was treated with fingolimod and had a favorable outcome 206 .

In one study, Hu et al. 208 evaluated leflunomide for COVID-19 treatment with a small cohort of patients, while the active metabolite of leflunomide, teriflunomide [ Fig. 10A (86) ], as an approved DHODH inhibitor, has been approved for treating autoimmune diseases 209 . They also proved that teriflunomide conferred a profound antiviral efficacy of IC 50 = 6 μmol/L in SARS-CoV-2-infected cells at MOI of 0.03 (Table 3 ). Clinical data show that patients treated with leflunomide had shorter viral shedding time (median of 5 days) than that of the controls (median of 11 days). The C-reactive protein levels of patients given leflunomide also decreased significantly, indicating that immunopathological inflammation was well controlled. In (Table 3) .

Homoharringtonine and emetine [ Fig. 10A (102, 103) Bojkova et al. 228 (Table 3) 228 . Pladienolide B [ Fig. 10A (105) ], a spliceosome inhibitor, targets the splicing factor SF3B1, which inhibited SARS-CoV-2 replication with an IC 50 of 0.007 μmol/L that were not toxic to human Caco-2 cells (Table 3) replication with an IC 50 of 0.17 μmol/L that are not toxic to human Caco-2 cells (Table 3) 228 .

AP-2-associated protein kinase 1 (AAK1) is a host kinase that regulates clathrin-mediated endocytosis 32 . Baricitinib [ Fig. 10A (109) ], a janus kinase inhibitor, is an AAK1-binding drug, which was supposed as a suitable drug candidate for COVID-19 because it can inhibit viral assembly by preventing AAK1-mediated endocytosis 232 . According to the EU Clinical Trials Register phases 2 and 3

(2020-001854-23), as well as phase-4 (2020-001354-22), clinical trials are now using baricitinib on COVID-19 patients (Table 3) . (Table   3) . Meanwhile, they demonstrated the in vivo antiviral activity of plitidepsin in two SARS-CoV-2 infected mouse models with reduced viral replication in the lungs.

Plitidepsin has also successfully completed a phase 1/2 clinical study for the treatment of COVID-19 (ClinicalTrials.gov, NCT04382066).

Nitric oxide (NO) is a gas with various biological activities produced by arginine through NO synthase. NO inhalation is beneficial for most patients with severe ARDS 240 and CC 50 of >> 50 μmol/L in Vero E6 cells by CellTiter-Glo assays (Table 3) (Table 3) .

According to the results of CCK-8 assay, the CC 50 values of these compounds were also calculated (Table 3) . Table 3 ). Their study also reported that treatment with panduratin A was able to inhibit viral infectivity in human airway epithelial cells.

Using cell-based infection assays, Jan et al. 94 Fig. 10B (157, 158) ] inhibited virus replication with IC 50 s of 180 and 198 nmol/L in A549-ACE2 cells, respectively (Table 3) .

Hopefully, clofazimine was verified to inhibit SARS-CoV-2 by its interference with viral membrane fusion and the function of helicase, as well as upregulated gene expression of innate immune-related pathways in cells 69 .

Despite tremendous global efforts, COVID-19 remains a serious concern. Although many clinical trials of the repurposed drugs, immune-based therapies and investigational antivirals have been conducted, there is still no highly effective therapeutic for treatment of COVID-19 available. The mutation and pandemic of SARS-CoV-2 make vaccine and drug discovery more uncertain. Accordingly, developing specific or broad-spectrum inhibitors for SARS-CoV-2 virus entry, replication or prevention is urgently needed. J o u r n a l P r e -p r o o f undergoes priming of the S1 subunit by relevant proteases to achieve the prefusion state. Subsequent triggering by relevant proteases will enable the FP to insert in the host membrane and allow the S protein to form the prehairpin intermediate. The

prehairpin begins to fold back on itself due to HR1 and HR2 interactions forming the 6-HB, and eventual postfusion stable states. During the S protein foldback, the two membranes will approach each other until the outer leaflets merge (hemifusion) and

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