Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors ofChikungunyansP2 Cysteine Protease with Anti-alphavirus Activity DOI Creative Commons
Anirban Ghoshal, Kesatebrhan Haile Asressu, Mohammad Anwar Hossain

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 13, 2024

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (

Language: Английский

Identification of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach DOI Creative Commons
Eric M. Merten, John D. Sears, Tina M. Leisner

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(42)

Published: Oct. 10, 2024

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics any infection. CHIKV nonstructural protein 2 (nsP2), which contains cysteine protease domain, essential viral replication, making it an attractive target drug discovery campaign. Here, we optimized nsP2 (nsP2pro) biochemical assay screening of 6,120-compound cysteine-directed covalent fragment library. Using 50% inhibition threshold, identified 153 hits (2.5% hit rate). In dose–response follow-up, RA-0002034, vinyl sulfone warhead, inhibited nsP2pro with IC 50 58 ± 17 nM, and further analysis time-dependent studies yielded k inact /K I 6.4 × 10 3 M −1 s . LC-MS/MS determined RA-0002034 covalently modified catalytic site-specific manner. Additionally, showed significant off-target reactivity proteomic experiments or against panel proteases. addition to potent activity exceptional selectivity, was tested cellular models infection effectively replication both related alphaviruses. This study highlights identification characterization chemical probe as promising compound from fragment-based development toward pan-alphavirus therapeutic.

Language: Английский

Citations

7
Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of Chikungunya nsP2 Cysteine Protease with Antialphavirus Activity DOI Creative Commons
Anirban Ghoshal, Kesatebrhan Haile Asressu, Mohammad Anwar Hossain

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 16505 - 16532

Published: Sept. 5, 2024

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (

Language: Английский

Citations

5
Species Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with in Vivo Anti-alphaviral Activity DOI Creative Commons
Mohammad Anwar Hossain,

A. Mayo,

Anirban Ghoshal

et al.

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

Published: Jan. 16, 2025

Abstract RA-0002034 ( 1 ) is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S -transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower observed human hepatocytes preclinical species such as rats, dogs, monkeys. Cross-species studies confirmed dominance GST-driven whereas oxidative pathways more pronounced dogs. Despite systemic clearance, achieved antiviral efficacy reducing CHIKV viral loads multiple tissues. Initial estimations hepatic half-life extrapolated from animal data indicate that b.i.d. dosing will be possible maintain concentrations sufficient for activity humans. These cross-species pharmacokinetic support continued evaluation promising anti-alphaviral therapeutic. Graphical

Language: Английский

Citations

0
A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity DOI Creative Commons
Anirban Ghoshal, Edwin G. Tse, Mohammad Anwar Hossain

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: March 1, 2025

Language: Английский

Citations

0
Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity DOI Creative Commons
Mohammad Anwar Hossain,

A. Mayo,

Anirban Ghoshal

et al.

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

Published: May 12, 2025

RA-0002034 (1) is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of 1 were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione S-transferase (GST)-catalyzed conjugation. This metabolic liability contrasted with slower observed human hepatocytes preclinical species, such as rats, dogs, monkeys. Cross-species studies confirmed dominance GST-driven whereas oxidative pathways more pronounced dogs. Despite systemic clearance, achieved antiviral efficacy reducing chikungunya (CHIKV) viral loads multiple tissues. These cross-species pharmacokinetic support continued evaluation potential antialphaviral further define contribution hepatic non-hepatic GST humans.

Language: Английский

Citations

0
Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors ofChikungunyansP2 Cysteine Protease with Anti-alphavirus Activity DOI Creative Commons
Anirban Ghoshal, Kesatebrhan Haile Asressu, Mohammad Anwar Hossain

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 13, 2024

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 (

Language: Английский

Citations

2