Macrocyclic Azapeptide Nitriles: Structure-Based Discovery of Potent SARS-CoV-2 Main Protease Inhibitors as Antiviral Drugs

Given the crucial role of the main protease (M-pro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M-pro. Our systematic approach combined...

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Published in:Journal of medicinal chemistry Vol. 67; no. 11; pp. 8757 - 8790
Main Authors: Breidenbach, Julian, Voget, Rabea, Si, Yaoyao, Hingst, Alexandra, Claff, Tobias, Sylvester, Katharina, Wolf, Valentina, Krasniqi, Vesa, Useini, Abibe, Straeter, Norbert, Ogura, Yukino, Kawaguchi, Atsushi, Mueller, Christa E., Guetschow, Michael
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 13.06.2024
Subjects:
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Chemistry, Medicinal
Coronavirus 3C Proteases - antagonists & inhibitors
Coronavirus 3C Proteases - chemistry
Coronavirus 3C Proteases - metabolism
COVID-19 Drug Treatment
Cysteine Proteinase Inhibitors - chemical synthesis
Cysteine Proteinase Inhibitors - chemistry
Cysteine Proteinase Inhibitors - pharmacology
Drug Discovery
Humans
Life Sciences & Biomedicine
Macrocyclic Compounds - chemical synthesis
Macrocyclic Compounds - chemistry
Macrocyclic Compounds - pharmacology
Nitriles - chemical synthesis
Nitriles - chemistry
Nitriles - pharmacology
Peptides - chemical synthesis
Peptides - chemistry
Peptides - pharmacology
Peptidomimetics - chemical synthesis
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Pharmacology & Pharmacy
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
SARS-CoV-2 - drug effects
Science & Technology
Structure-Activity Relationship
PLASMA STABILITY
COVALENT INHIBITORS
ATROPISOMERISM
MECHANISM
CORONAVIRUS
ISSN:0022-2623, 1520-4804, 1520-4804
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Summary:Given the crucial role of the main protease (M-pro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of M-pro. Our systematic approach combined an M-pro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent M-pro inhibitor 84 with an IC50 value of 3.23 nM and a second-order rate constant of inactivation, k(inac)/K-i, of 448,000 M(-1)s(-1). The open-chain M-pro inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC50 values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic M-pro inhibitors as anti-SARS-CoV-2 agents.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.4c00053