A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

Macip, Guillem; Garcia-Segura, Pol; Mestres-Truyol, Júlia; Saldivar-Espinoza, Bryan; Pujadas, Gerard; Garcı́a-Vallvé, Santiago

doi:10.3390/ijms23010259

Cited by 38 publications

(44 citation statements)

References 108 publications

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“…To date, thousands of candidate SARS-CoV-2 Mpro inhibitor compounds have been screened so far in order to identify potent drug candidates [ 64 ], but many of them were shown to have no or only limited clinical potential since high concentration was usually required to achieve significant inhibition. Actually, most of the investigational 3CLpro inhibitors are of similar peptidomimetic scaffolds [ 65 ].…”

Section: Proteases Inhibitors and Mutationsmentioning

confidence: 99%

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Mótyán

Mahdi

Hoffka

et al. 2022

IJMS

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Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The lack of potent novel antivirals had led to global health crises; however, emergence and approval of potent inhibitors of the viral main protease (Mpro), such as Pfizer’s newly approved nirmatrelvir, offers hope not only in the therapeutic front but also in the context of prophylaxis against the infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, and lessons learnt from previous and currently ongoing pandemics have taught us that these viruses can easily escape selection pressure through mutation of vital target amino acid residues in monotherapeutic settings. In this paper, we review nirmatrelvir and its binding to SARS-CoV-2 Mpro and draw a comparison to inhibitors of HIV protease that were rendered obsolete by emergence of resistance mutations, emphasizing potential pitfalls in the design of inhibitors that may be of important relevance to the long-term use of novel inhibitors against SARS-CoV-2.

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Section: Proteases Inhibitors and Mutationsmentioning

confidence: 99%

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Mótyán

Mahdi

Hoffka

et al. 2022

IJMS

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“…[55,56] Several different types of inhibitors have been investigated including peptidomimetic covalent inhibitors, small molecule covalent inhibitors, and noncovalent inhibitors. [9,57] Historically, covalent inhibitors were thought to be generally cytotoxic due to off target effects; however, recent developments have shown that this is not always the case. Development of covalent cysteine proteases has shown significant potential for SARS-CoV-2 drug development.…”

Section: Sars-cov-2 3clpro Inhibitorsmentioning

confidence: 99%

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

et al. 2022

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COVID‐19, caused by SARS‐CoV‐2 infection, continues to be a major public health crisis around the globe. Development of vaccines and the first cluster of antiviral drugs has brought promise and hope for prevention and treatment of severe coronavirus disease. However, continued development of newer, safer, and more effective antiviral drugs are critically important to combat COVID‐19 and counter the looming pathogenic variants. Studies of the coronavirus life cycle revealed several important biochemical targets for drug development. In the present review, we focus on recent drug design and medicinal chemistry efforts on small molecule drug discovery including the development of nirmatrelvir that targets viral protein synthesis and remdesivir and molnupiravir that target viral RdRp. These are recent FDA approved drugs for the treatment of COVID‐19.

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“…Paxlovid, an oral SARS-CoV-2 M pro inhibitor, was recently approved to treat mild-to-moderate COVID-19 [41]. Many review articles show the effort put in to identify the most effective covalent and non-covalent inhibitors of the SARS-CoV-2 M pro [3,42,43]. All these studies show that M pro is one of the most promising viral targets for SARS-CoV-2 antiviral drug development.…”

Section: Introductionmentioning

confidence: 99%

In Silico Analysis Using SARS-CoV-2 Main Protease and a Set of Phytocompounds to Accelerate the Development of Therapeutic Components against COVID-19

2022

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SARS-CoV-2, the virus that caused the widespread COVID-19 pandemic, is homologous to SARS-CoV. It would be ideal to develop antivirals effective against SARS-CoV-2. In this study, we chose one therapeutic target known as the main protease (Mpro) of SARS-CoV-2. A crystal structure (Id: 6LU7) from the protein data bank (PDB) was used to accomplish the screening and docking studies. A set of phytocompounds was used for the docking investigation. The nature of the interaction and the interacting residues indicated the molecular properties that are essential for significant affinity. Six compounds were selected, based on the docking as well as the MM-GBSA score. Pentagalloylglucose, Shephagenin, Isoacteoside, Isoquercitrin, Kappa-Carrageenan, and Dolabellin are the six compounds with the lowest binding energies (−12 to −8 kcal/mol) and show significant interactions with the target Mpro protein. The MMGBSA scores of these compounds are highly promising, and they should be investigated to determine their potential as Mpro inhibitors, beneficial for COVID-19 treatment. In this study, we highlight the crucial role of in silico technologies in the search for novel therapeutic components. Computational biology, combined with structural biology, makes drug discovery studies more rigorous and reliable, and it creates a scenario where researchers can use existing drug components to discover new roles as modulators or inhibitors for various therapeutic targets. This study demonstrated that computational analyses can yield promising findings in the search for potential drug components. This work demonstrated the significance of increasing in silico and wetlab research to generate improved structure-based medicines.

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A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

Cited by 38 publications

References 108 publications

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

Potential Resistance of SARS-CoV-2 Main Protease (Mpro) against Protease Inhibitors: Lessons Learned from HIV-1 Protease

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

In Silico Analysis Using SARS-CoV-2 Main Protease and a Set of Phytocompounds to Accelerate the Development of Therapeutic Components against COVID-19

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