Improved Synthesis of a Cyclic Glutamine Analogue Used in Antiviral Agents Targeting 3C and 3CL Proteases Including SARS-CoV-2 Mpro.
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ABSTRACT:
SUBMITTER: Vuong W
PROVIDER: S-EPMC8425337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We prepared the three-dimensional model of the SARS-CoV-2 (aka 2019-nCoV) 3C-like protease (3CL pro) using the crystal structure of the highly similar (96% identity) ortholog from the SARS-CoV. All residues involved in the catalysis, substrate binding and dimerisation are 100% conserved. Comparison of the polyprotein PP1AB sequences showed 86% identity. The 3C-like cleavage sites on the coronaviral polyproteins are highly conserved. Based on the near-identical substrate specificities and high sequence identities, we are of the opinion that some of the previous progress of specific inhibitors development for the SARS-CoV enzyme can be conferred on its SARS-CoV-2 counterpart. With the 3CL pro molecular model, we performed virtual screening for purchasable drugs and proposed 16 candidates for consideration. Among these, the antivirals ledipasvir or velpatasvir are particularly attractive as therapeutics to combat the new coronavirus with minimal side effects, commonly fatigue and headache. The drugs Epclusa (velpatasvir/sofosbuvir) and Harvoni (ledipasvir/sofosbuvir) could be very effective owing to their dual inhibitory actions on two viral enzymes.
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Project description:The sudden increase in the COVID-19 epidemic affected by novel coronavirus 2019 has jeopardized public health worldwide. Hence the necessities of a drug or therapeutic agent that heal SARS-CoV-2 infections are essential requirements. The viral genome encodes a large Polyprotein, further processed by the main protease/ 3C-like protease (3CLpro) and papain-like proteases (PLpro) into 16 nonstructural proteins to form a viral replication complex. These essential functions of 3CLpro and PLpro in virus duplication make these proteases a promising target for discovering potential therapeutic candidates and possible treatment for SARS-CoV-2 infection. This study aimed to screen a unique set of protease inhibitors library against 3CLpro and PLpro of the SARS-CoV-2. A molecular docking study was performed using PyRx to reveal the binding affinity of the selected ligands and molecular dynamic simulations were executed to assess the three-dimensional stability of protein-ligand complexes. The pharmacodynamics parameters of the inhibitors were predicted using admetSAR. The top two ligands (Nafamostat and VR23) based on docking scores were selected for further studies. Selected ligands showed excellent pharmacokinetic properties with proper absorption, bioavailability and minimal toxicity. Due to the emerging and efficiency of remdesivir and dexamethasone in healing COVID-19 patients, ADMET properties of the selected ligands were thus compared with it. MD Simulation studies up to 100 ns revealed the ligands' stability at the target proteins' binding site residues. Therefore, Nafamostat and VR23 may provide potential treatment options against SARS-CoV-2 infections by potentially inhibiting virus duplication though more research is warranted.
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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is an unprecedented global health emergency causing more than 4.2 million fatalities as of 30 July 2021. Only three antiviral therapies have been approved or granted emergency use authorization by the FDA. The SARS-CoV-2 3CL protease (3CLpro ) is deemed an attractive drug target as it plays an essential role in viral polyprotein processing and pathogenesis, although no inhibitors have been approved. This patent review discusses SARS coronavirus 3CLpro inhibitors that have been filed up to 30 July 2021, giving an overview on the types of inhibitors that have generated commercial interest, especially amongst drug companies. Insights into the common structural motifs required for active site binding is also discussed.
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Project description:The main protease, Mpro, of SARS-CoV-2 is required to cleave the viral polyprotein into precise functional units for virus replication and pathogenesis. Here, we report quantitative reporters for Mpro function in living cells in which protease inhibition by genetic or chemical methods results in robust signal readouts by fluorescence (enhanced green fluorescent protein [eGFP]) or bioluminescence (firefly luciferase). These gain-of-signal systems are scalable to high-throughput platforms for quantitative discrimination between Mpro mutants and/or inhibitor potencies as evidenced by validation of several reported inhibitors. Additional utility is shown by single Mpro amino acid variants and structural information combining to demonstrate that both inhibitor conformational dynamics and amino acid differences are able to influence inhibitor potency. We further show that a recent variant of concern (Omicron) has an unchanged response to a clinically approved drug, nirmatrelvir, whereas proteases from divergent coronavirus species show differential susceptibility. Together, we demonstrate that these gain-of-signal systems serve as robust, facile, and scalable assays for live cell quantification of Mpro inhibition, which will help expedite the development of next-generation antivirals and enable the rapid testing of emerging variants. IMPORTANCE The main protease, Mpro, of SARS-CoV-2 is an essential viral protein required for the earliest steps of infection. It is therefore an attractive target for antiviral drug development. Here, we report the development and implementation of two complementary cell-based systems for quantification of Mpro inhibition by genetic or chemical approaches. The first is fluorescence based (eGFP), and the second is luminescence based (firefly luciferase). Importantly, both systems rely upon gain-of-signal readouts such that stronger inhibitors yield higher fluorescent or luminescent signal. The high versatility and utility of these systems are demonstrated by characterizing Mpro mutants and natural variants, including Omicron, as well as a panel of existing inhibitors. These systems rapidly, safely, and sensitively identify Mpro variants with altered susceptibilities to inhibition, triage-nonspecific, or off-target molecules and validate bona fide inhibitors, with the most potent thus far being the first-in-class drug nirmatrelvir.
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