Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS‐CoV‐2 Infection and COVID‐19

Ghosh, Arun K.; Mishevich, Jennifer L.; Mesecar, Andrew D.; Mitsuya, Hiroaki

doi:10.1002/cmdc.202200440

Cited by 43 publications

(38 citation statements)

References 144 publications

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“…The morbidity and mortality associated with the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are continuing to have a major impact on public health and the global economy. − The timely discovery and introduction into the clinic of effective vaccines and monoclonal antibodies have ameliorated the impact and threat of the disease; , however, there is a pressing need for the development of effective and complementary countermeasures, including an expanded and diversified portfolio of direct-acting antivirals (DAAs) − that can be rapidly deployed against SARS-CoV-2 and variants, as well as emerging and re-emerging coronaviruses. , …”

mentioning

confidence: 99%

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Dampalla

Nguyen

Rathnayake

et al. 2022

ACS Pharmacol. Transl. Sci.

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The advent of SARS-CoV-2, the causative agent of COVID-19, and its worldwide impact on global health, have provided the impetus for the development of effective countermeasures that can be deployed against the virus, including vaccines, monoclonal antibodies, and direct-acting antivirals (DAAs). Despite these efforts, the current paucity of DAAs has created an urgent need for the creation of an enhanced and diversified portfolio of broadly acting agents with different mechanisms of action that can effectively abrogate viral infection. SARS-CoV-2 3C-like protease (3CL pro ), an enzyme essential for viral replication, is a validated target for the discovery of SARS-CoV-2 therapeutics. In this report, we describe the structure-guided utilization of the cyclopropane moiety in the design of highly potent inhibitors of SARS-CoV-2 3CL pro , SARS-CoV-1 3CL pro , and MERS-CoV 3CL pro . High-resolution cocrystal structures were used to identify the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and unravel the mechanism of action. Aldehydes 5c and 11c inhibited SARS-CoV-2 replication with EC 50 values of 12 and 11 nM, respectively. Furthermore, the corresponding aldehyde bisulfite adducts 5d and 11d were equipotent with EC 50 values of 13 and 12 nM, respectively. The safety index (SI) values for compounds 5c/11c and 5d/11d ranged between 7692 and 9090. Importantly, aldehydes 5c/11c and bisulfite adducts 5d/11d potently inhibited MERS-CoV 3CL pro with IC 50 values of 80 and 120 nM, and 70 and 70 nM, respectively. Likewise, compounds 5c/11c and 5d/11d inhibited SARS-CoV-1 with IC 50 values of 960 and 350 nM and 790 and 240 nM, respectively. Taken together, these studies suggest that the inhibitors described herein have low cytotoxicity and high potency and are promising candidates for further development as broad-spectrum direct-acting antivirals against highly pathogenic coronaviruses.

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confidence: 99%

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Dampalla

Nguyen

Rathnayake

et al. 2022

ACS Pharmacol. Transl. Sci.

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“…Many of the large-scale studies have employed low-resolution techniques such as mass spectroscopy 5,27,30,47,[56][57][58] that provide information on binary interactions as well as on larger complexes. Furthermore, several studies aimed to identify potential inhibitors of viral infection, mainly targeting RNA-dependent-RNA polymerase [59][60][61][62] and the proteases [63][64][65] , or producing antibodies against spike protein [66][67][68][69][70] . However, to increase the likelihood of successful drug development, efforts need to be extended to include other SARS-CoV-2…”

Section: Peptide Ligands Targeting Nsp3 Adrp Nsp9 and Nsp16 Inhibit V...mentioning

confidence: 99%

Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets

Mihalič

Benz

Kassa

et al. 2022

Preprint

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The infection and replication cycle of all viruses depend on interactions between viral and host proteins. Each of these protein-protein interactions is therefore a potential drug target. These host-virus interactions often involve a disordered protein region on one side of the interface and a folded protein domain on the other. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind peptides from human proteins. Of 281 high/medium confidence peptides, 23 interactions involving eight SARS-CoV-2 protein domains were tested by fluorescence polarization, and binding was observed with affinities spanning the whole micromolar range. The key specificity determinants were established for six of these domains, two based on ProP-PD and four by alanine scanning SPOT arrays. Finally, two cell-penetrating peptides, targeting Nsp9 and Nsp16, respectively, were shown to function as inhibitors of viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously provide information on potential host-virus interactions and identify ligands with antiviral properties.

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“…There are three FDA-approved antiviral drugs, remdesivir, molnupiravir, and paxlovid. 9 Remdesivir and molnupiravir are viral RNA-dependent RNA polymerase (RdRp) inhibitors that were discovered from a drug repurposing approach. Paxlovid is a combination of the SARS-CoV-2 M pro inhibitor nirmatrelvir and its metabolic enhancer ritonavir.…”

Section: Introductionmentioning

confidence: 99%

“…There are three FDA-approved antiviral drugs, remdesivir, molnupiravir, and paxlovid . Remdesivir and molnupiravir are viral RNA-dependent RNA polymerase (RdRp) inhibitors that were discovered from a drug repurposing approach.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies

et al. 2022

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Conspectus SARS-CoV-2 is the etiological pathogen of the COVID-19 pandemic, which led to more than 6.5 million deaths since the beginning of the outbreak in December 2019. The unprecedented disruption of social life and public health caused by COVID-19 calls for fast-track development of diagnostic kits, vaccines, and antiviral drugs. Small molecule antivirals are essential complements of vaccines and can be used for the treatment of SARS-CoV-2 infections. Currently, there are three FDA-approved antiviral drugs, remdesivir, molnupiravir, and paxlovid. Given the moderate clinical efficacy of remdesivir and molnupiravir, the drug–drug interaction of paxlovid, and the emergence of SARS-CoV-2 variants with potential drug-resistant mutations, there is a pressing need for additional antivirals to combat current and future coronavirus outbreaks. In this Account, we describe our efforts in developing covalent and noncovalent main protease (M pro ) inhibitors and the identification of nirmatrelvir-resistant mutants. We initially discovered GC376, calpain inhibitors II and XII, and boceprevir as dual inhibitors of M pro and host cathepsin L from a screening of a protease inhibitor library. Given the controversy of targeting cathepsin L, we subsequently shifted the focus to designing M pro -specific inhibitors. Specifically, guided by the X-ray crystal structures of these initial hits, we designed noncovalent M pro inhibitors such as Jun8-76-3R that are highly selective toward M pro over host cathepsin L. Using the same scaffold, we also designed covalent M pro inhibitors with novel cysteine reactive warheads containing di- and trihaloacetamides, which similarly had high target specificity. In parallel to our drug discovery efforts, we developed the cell-based FlipGFP M pro assay to characterize the cellular target engagement of our rationally designed M pro inhibitors. The FlipGFP assay was also applied to validate the structurally disparate M pro inhibitors reported in the literature. Lastly, we introduce recent progress in identifying naturally occurring M pro mutants that are resistant to nirmatrelvir from genome mining of the nsp5 sequences deposited in the GISAID database. Collectively, the covalent and noncovalent M pro inhibitors and the nirmatrelvir-resistant hot spot residues from our studies provide insightful guidance for future work aimed at developing orally bioavailable M pro inhibitors that do not have overlapping resistance profile with nirmatrelvir.

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Recent Drug Development and Medicinal Chemistry Approaches for the Treatment of SARS‐CoV‐2 Infection and COVID‐19

Cited by 43 publications

References 144 publications

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Broad-Spectrum Cyclopropane-Based Inhibitors of Coronavirus 3C-like Proteases: Biochemical, Structural, and Virological Studies

Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets

SARS-CoV-2 Main Protease Drug Design, Assay Development, and Drug Resistance Studies

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