Structure and function of SARS-CoV and SARS-CoV-2 main proteases and their inhibition: A comprehensive review

Li, Xin; Song, Yongcheng

doi:10.1016/j.ejmech.2023.115772

Cited by 40 publications

(11 citation statements)

References 298 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many reports have already listed all the, sometimes related, 36 inhibitors reported for their effect on chymotrypsin-like proteases of human rhinovirus, 37–40 enterovirus 71, 41 SARS and MERS coronaviruses 42–46 and then SARS-CoV-2. 2–4,6,17,18,47–70 In the present text, the many publications 26 solely based on in silico docking approaches 71,72 and/or on traditional/ancestral medicine beliefs which only described frequent hitters/pan-assay interference compounds (PAINS) 73–77 were ignored. This choice is a bid to discourage such all too obvious pollution of the scientific literature, 78,79 not to mention the issue of lack of reproducibility of some data from the academia.…”

Section: Introductionmentioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

On the origins of SARS-CoV-2 main protease inhibitors

Janin

2024

RSC Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Given its essential role in the viral life cycle in conjunction with the absence of closely related homologs in the human genome, drug discovery targeting 3CL pro has been a pivotal research area during the SARS-CoV-2 pandemic, and several 3CL pro inhibitors have been identified [11][12][13][14] . These molecules can be categorized into two large families, namely i) peptidomimetics, and ii) non-peptide small molecules.…”

Section: Introductionmentioning

confidence: 99%

An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease

Mazzei,

Ranieri,

Greene-Cramer

et al. 2024

Preprint

View full text Add to dashboard Cite

This manuscript describes the application of Isothermal Titration Calorimetry (ITC) to characterize the kinetics of 3CLprofrom the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and its inhibition by Ensitrelvir, a known non-covalent inhibitor. 3CLprois the main protease that plays a crucial role of producing the whole array of proteins necessary for the viral infection that caused the spread of COVID-19, responsible for millions of deaths worldwide as well as global economic and healthcare crises in recent years. The proposed calorimetric method proved to have several advantages over the two types of enzymatic assays so far applied to this system, namely Förster Resonance Energy Transfer (FRET) and Liquid Chromatography-Mass Spectrometry (LC-MS). The developed ITC-based assay provided a rapid response to 3CLproactivity, which was used to directly derive the kinetic enzymatic constantsKMandkcatreliably and reproducibly, as well as their temperature dependence, from which the activation energy of the reaction was obtained for the first time. The assay further revealed the existence of two modes of inhibition of 3CLproby Ensitrelvir, namely a competitive mode as previously inferred by crystallography as well as an unprecedented uncompetitive mode, further yielding the respective inhibition constants with high precision. The calorimetric method described in this paper is thus proposed to be generally and widely used in the discovery and development of drugs targeting 3CLpro.

show abstract

“…Indeed Cys145 of M pro reacts reversibly with the nitrile group of the clinically-used drugs 1 and 2. 14,15,42 Many investigational M pro inhibitors, however, employ highly reactive electrophiles for covalent reaction with Cys145, including e.g., aldehydes, a-ketoamides, and Michael acceptors, 19,43,44 which may potentially compromise safety, as reported for some clinically-used small-molecules bearing reactive electrophiles; 26,45 The use of electrophilic groups with relatively low intrinsic reactivity is thus desirable. The observation that the glactam of both 1 and 2 is stable in cells 14,15 likely reects its reduced reactivity compared to more reactive electrophiles, indicating that covalently reacting g-lactams may have potential for development of safe COVID-19 therapeutics.…”

Section: Introductionmentioning

confidence: 99%