Abstract:This review fully describes the coronavirus 3CL
pro
peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CL
pro
inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CL
pro
Cys145 residue and thereby achieve irrever… Show more
“…Inhibitors possessing sub-µM affinity to M pro typically mimic Gln by introducing a lactam functionality as their P1 substituent in order to engage His163 in a hydrogen bond. 39 Telaprevir features a hydrophobic norvaline substituent in P1 position that cannot make hydrogen bonds in subsite S1. Compared to the ligand-free structure, inhibitor binding leads to the recruitment of a water molecule into subsite S1.…”
The main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the α-ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other α-ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.
“…Inhibitors possessing sub-µM affinity to M pro typically mimic Gln by introducing a lactam functionality as their P1 substituent in order to engage His163 in a hydrogen bond. 39 Telaprevir features a hydrophobic norvaline substituent in P1 position that cannot make hydrogen bonds in subsite S1. Compared to the ligand-free structure, inhibitor binding leads to the recruitment of a water molecule into subsite S1.…”
The main protease (3CL Mpro) from SARS-CoV-2, the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. Although drugs have been developed to inhibit the proteases from HIV, hepatitis C and other viruses, no such therapeutic is available to inhibit the main protease of SARS-CoV-2. To directly observe the protonation states in SARS-CoV-2 Mpro and to elucidate their importance in inhibitor binding, we determined the structure of the enzyme in complex with the α-ketoamide inhibitor telaprevir using neutron protein crystallography at near-physiological temperature. We compared protonation states in the inhibitor complex with those determined for a ligand-free neutron structure of Mpro. This comparison revealed that three active-site histidine residues (His41, His163 and His164) adapt to ligand binding, altering their protonation states to accommodate binding of telaprevir. We suggest that binding of other α-ketoamide inhibitors can lead to the same protonation state changes of the active site histidine residues. Thus, by studying the role of active site protonation changes induced by inhibitors we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.
“…Therefore, the lung tropism of 9 is a favourable target organ feature. A mouse lung drug inhalation model showed that 9 is well tolerated without adverse reactions; hence, lung inhalation is the appropriate method for the administration of 9 [ 41 ]. Fig.…”
Section: Coronavirus Non-structural Protein Inhibitorsmentioning
“…It was found that NPs/SMs are a rich source of drug potential leads against coronaviruses due to their pronounced structural diversity and complexity. Several compilations of pre-2020 findings on NPs/SMs with activity against coronaviruses were recently reported, some of which could serve as leads for the development of new drugs [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Among the identified molecules the majority is represented by NPs ( Figure 2 a) and most of them have been found as inhibitors of SARS-CoV ( Figure 2 b).…”
The ongoing pandemic of severe acute respiratory syndrome (SARS), caused by the SARS-CoV-2 human coronavirus (HCoV), has brought the international scientific community before a state of emergency that needs to be addressed with intensive research for the discovery of pharmacological agents with antiviral activity. Potential antiviral natural products (NPs) have been discovered from plants of the global biodiversity, including extracts, compounds and categories of compounds with activity against several viruses of the respiratory tract such as HCoVs. However, the scarcity of natural products (NPs) and small-molecules (SMs) used as antiviral agents, especially for HCoVs, is notable. This is a review of 203 publications, which were selected using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, evaluates the available literature since the discovery of the first human coronavirus in the 1960s; it summarizes important aspects of structure, function, and therapeutic targeting of HCoVs as well as NPs (19 total plant extracts and 204 isolated or semi-synthesized pure compounds) with anti-HCoV activity targeting viral and non-viral proteins, while focusing on the advances on the discovery of NPs with anti-SARS-CoV-2 activity, and providing a critical perspective.
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