How Polyproline Type II Conformation at P2 Residues Influences the Success of Proline-Based Peptidyl Inhibitors Against Coronavirus Main Protease DOI
Pathum M. Weerawarna

Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 30, 2024

In the wake of pandemic, peptidyl protease inhibitors with Pro-based rigid Leu mimetics at P2 position have emerged as potent drug candidates against SARS-CoV-2 main protease. This success is intuitively attributed to enhanced hydrophobic interactions and rigidity in literature. However, tertiary amide proline derivatives, which hinders formation a critical hydrogen bond enzyme active site, constrained PPII conformation, contradicts preferred β-strand represent two overlooked disadvantages associated these over traditional and, theoretically, should adversely affect their potency. Interestingly, despite major disadvantages, they maintain or display improved potency compared inhibitors. this study, we uncover previously unnoticed preference for residues adopt regardless residue identity, protease-bound form key RNA viruses, deviating from conformation. We also demonstrate that enhance binding affinity by favoring enzyme-preferred conformation significantly reducing configurational entropy loss upon binding, comparable typical bond. work highlights importance multidisciplinary approach understanding structure-activity relationships beyond medicinal chemistry intuition. believe findings provide new, deep insights address knowledge gap area inhibitor design, identifying drivers behind mere hydrophobicity.

Language: Английский

Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents DOI Creative Commons
Agnieszka Zagórska, Anna Czopek,

Monika Fryc

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 797 - 797

Published: July 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Language: Английский

Citations

9
Design of quinoline SARS-CoV-2 papain-like protease inhibitors as oral antiviral drug candidates DOI Creative Commons
Prakash D. Jadhav,

Xueying Liang,

Ahmadullah Ansari

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 13, 2025

The ever-evolving SARS-CoV-2 variants necessitate the development of additional oral antivirals. This study presents systematic design quinoline-containing papain-like protease (PLpro) inhibitors as potential antiviral drug candidates. By leveraging recently discovered Val70Ub binding site in PLpro, we designed a series quinoline analogs demonstrating potent PLpro inhibition and activity. Notably, X-ray crystal structures 6 lead compounds reveal that 2-aryl substitution can occupy either expected or BL2 groove flipped orientation. vivo Jun13296 exhibits favorable pharmacokinetic properties against nirmatrelvir-resistant mutants. In mouse model infection, treatment with significantly improves survival, reduces body weight loss lung viral titers, prevents tissue damage. These results underscore promising candidates, instilling hope for future treatment. inhibitor, Jun13296, displays efficacy infection inhibits mutants, rendering it candidate.

Language: Английский

Citations

1
Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro) DOI Creative Commons
Yue Yang,

Yidan Luo,

Chenbo Zhang

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(32), P. 34196 - 34219

Published: Aug. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Language: Английский

Citations

6
A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV DOI Creative Commons
Pu Chen, Tayla J. Van Oers, Elena Arutyunova

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(8), P. 3217 - 3227

Published: July 30, 2024

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from USA Food Drug Administration (FDA) entered phase III clinical trials as a possible replacement Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M

Language: Английский

Citations

4
Psoralidin acts as a dual protease inhibitor against PLpro and Mpro of SARS‐CoV‐2 DOI Open Access
Aditya Trivedi, Tushar Kushwaha, Areef Ishani

et al.

FEBS Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

The emergence of new coronavirus variants and concerns about vaccine effectiveness against these novel emphasize the need for broad‐spectrum therapeutics targeting conserved coronaviral non‐structural proteins. Accordingly, a virtual library 178 putative inhibitors SARS‐CoV‐2 Papain‐like protease (PL pro ) was compiled through systematic review published literature subsequently screened using molecular docking. Selected hits were analyzed inhibitory activities, binding strength, antiviral activities HCoV229E‐based surrogate system validation. Differences in potential modes action investigated an system, combined with silico biophysical methods system. Of hits, 13 molecules showed superior docking scores PL met inclusion criteria further investigations. these, seven notable . Particularly, both Psoralidin Corylifol‐A exhibited and, importantly, dual M Both found to be biologically active HCoV229E SARS‐CoV‐2; however, more consistent effects relatively well‐tolerated. Detailed analyses their interactions two proteases identified differences action, primarily due Based on findings, we propose as candidate development ideal lead optimization.

Language: Английский

Citations

0
Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity DOI

Philipp Flury,

Nadine Krüger,

Katharina Sylvester

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development antiviral therapeutics. Here, we designed and synthesized series small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent Mpro inhibitors, including 8n (IC50 = 0.0752 μM), 8p 0.0887 8r 0.0199 10a 0.0376 10c 0.0177 10f 0.0130 μM). Most them additionally inhibited cathepsin L also active against SARS-CoV-1 MERS-CoV Mpro. In Calu-3 cells, several 8r, 10a, 10c, displayed high activity in nanomolar range without showing cellular toxicity. cocrystal structure complex revealed covalent binding to enzyme's catalytic residue Cys145 showed specific, unprecedented interactions within substrate pocket. Compounds especially effective panel naturally occurring nirmatrelvir-resistant mutants, particularly E166V, metabolic stability additional favorable pharmacokinetic properties, making it suitable candidate further preclinical development.

Language: Английский

Citations

0
Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease DOI Creative Commons
A. Ravi Kumar, Haifa El Kilani,

Alina Metzen

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 16, 2025

The main protease Mpro is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among first reported inhibitors was peptidomimetic α-ketoamide 13b, whose cocrystal structure with paved way for multiple lead-finding studies. We established structure-activity relationships 13b series modifying residues at P1', P3, and P4 sites. Guided structures, we reduced P1' substituent size better fill pocket added fluorine pyridone ring, enabling new hydrogen bond Gln189 in P3. 22 novel analogues, 6d 12d inhibited IC50s of 110 nM 40 nM, improving potency up 9.5-fold. Compound had pronounced antiviral activity an EC50 1.6 μM stable plasma microsomes. study illustrates potential structure-based design systematically improve α-ketoamides.

Language: Английский

Citations

0
Discovery of The Clinical Candidate S-892216: A Second-Generation of SARS-CoV-2 3CL Protease Inhibitor for Treating COVID-19 DOI Open Access
Yuto Unoh,

Keiichiro Hirai,

Shota Uehara

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Abstract The coronavirus disease 2019 (COVID-19) pandemic crisis has been mitigated by worldwide efforts to develop vaccines and therapeutic drugs. However, there remains concern regarding public health an unmet need for options. Herein, we report the discovery of S-892216 , a second-generation SARS-CoV-2 3C-like protease (3CL pro ) inhibitor, treat COVID-19. is reversible covalent 3CL inhibitor with highly potent antiviral activity EC 50 value 2.48 nM against infected cells. Structure-based design modifier compound 1 revealed that introducing nitrile warhead increased inhibition 180-fold. Subsequent optimization yielded which combined favorable pharmacokinetic profile high off-target selectivity. exhibited diverse variants, no cross-resistance major mutations reducing activities nirmatrelvir ensitrelvir. In SARS-CoV-2-infected mice, inhibited viral replication in lungs similar ensitrelvir, although at 30-fold lower dose.

Language: Английский

Citations

0
A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID DOI Creative Commons
Stefanie M. Bader, Dale J. Calleja, Shane M. Devine

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 3, 2025

Language: Английский

Citations

0
Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies DOI Creative Commons

Dóra Laczi,

Sofia Schönbauer Huamán,

Taylah Andrews-Clark

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 117603 - 117603

Published: April 1, 2025

Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that clinically used in combination with ritonavir to treat COVID-19. Derivatives nirmatrelvir, modified at substrate P2-equivalent position, have been developed fine-tune properties and are now clinical use. We report synthesis nirmatrelvir derivatives (R)-4,4-dimethyl-4-silaproline (silaproline) group position. Mass spectrometry (MS)-based assays demonstrate silaproline-bearing efficiently inhibit isolated recombinant Mpro, albeit reduced potency compared nirmatrelvir. Investigations SARS-CoV-2 infected VeroE6 cells reveal inhibitors CF3 P4-equivalent position viral progression, implying incorporating silicon atoms into Mpro can yield vivo active appropriate optimization. MS crystallographic studies show nucleophilic site cysteine residue (Cys145) reacts nitrile inhibitors. Substituting electrophilic for non-activated terminal alkyne shifts inhibition mode from reversible covalent irreversible inhibition. One two prochiral silaproline methyl groups occupies space S2 pocket unoccupied Mpro:nirmatrelvir complex structures, highlighting value sila-derivatives structure-activity-relationship (SAR) studies. The combined results highlight potential silicon-containing molecules and, by implication, other enzymes.

Language: Английский

Citations

0