Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency DOI Creative Commons
Alexandre Joushomme, Antoine Désilets,

William Champagne

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and cell entry respiratory viruses. To date, no inhibitors have been specifically developed toward this protease. In study, chemical library 65 ketobenzothiazole-based peptidomimetic molecules was screened against proteolytically active form recombinant TMPRSS13 to identify novel inhibitors. Following an initial round screening, subsequent synthesis additional derivatives supported by molecular modelling, uncovered important determinants inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards activity cellular context. Using SARS-CoV-2 pseudovirus model, we further show ability N-0430 block TMPRSS13-dependent pseudovirus. The identified insights their potency gained from study will aid development specific

Язык: Английский

Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency DOI Creative Commons
Alexandre Joushomme, Antoine Désilets,

William Champagne

и другие.

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2025, Номер 40(1)

Опубликована: Фев. 20, 2025

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and respiratory virus cell entry. To date, no inhibitors have been specifically developed for this protease. In study, chemical library 65 ketobenzothiazole-based peptidomimetic molecules was screened against proteolytically active form recombinant TMPRSS13 to identify novel inhibitors. Following an initial round screening, subsequent synthesis additional derivatives supported by molecular modelling revealed important determinants inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards activity cellular context. Using SARS-CoV-2 pseudovirus entry model, we further demonstrated ability N-0430 block TMPRSS13-dependent pseudovirus. The identified insights into their potency gained from study will aid development specific

Язык: Английский

Процитировано

1
TMPRSS2 as a Key Player in Viral Pathogenesis: Influenza and Coronaviruses DOI Creative Commons
Gilmara Barros de Lima,

Everton Nencioni,

Fábio Thimoteo

и другие.

Biomolecules, Год журнала: 2025, Номер 15(1), С. 75 - 75

Опубликована: Янв. 7, 2025

TMPRSS2, a human transmembrane protease enzyme, plays crucial role in the spread of certain viruses, including influenza and coronaviruses. This enzyme promotes viral infection by cleaving glycoproteins, which helps viruses like SARS-CoV-2 A enter cells more effectively. Genetic differences TMPRSS2 may affect people’s susceptibility to COVID-19, underscoring need for studies that consider diverse populations. Beyond infectious diseases, has also been linked some cancers, suggesting it could be valuable target drug development. review provides summary inhibitors currently under study, with already clinical trials test their effectiveness against infections. As we uncover about TMPRSS2’s pathogenesis, open new doors therapies combat future outbreaks.

Язык: Английский

Процитировано

0
Optimizing the Pharmacokinetics and Selectivity of TMPRSS2 Inhibitors DOI

Sára Ferková,

Matthieu Lepage,

Antoine Désilets

и другие.

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown, С. 117579 - 117579

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0
From N-0385 to N-0920: Unveiling a Host-Directed Protease Inhibitor with Picomolar Antiviral Efficacy against Prevalent SARS-CoV-2 Variants DOI
Gabriel Lemieux, Jimena Pérez‐Vargas, Antoine Désilets

и другие.

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 31, 2025

The worldwide spread of new SARS-CoV-2 variants emphasizes the need to diversify existing therapeutic strategies. TMPRSS2, a host protease crucial for entry, has garnered significant research attention as potential target intervention. Here, we optimized N-0385, previously reported TMPRSS2 ketobenzothiazole-based peptidomimetic inhibitor, by screening 135 derivatives affinity and antiviral potency. Among top candidates, N-0695 exhibited low nanomolar Ki values against three TTSPs associated with respiratory virus entry: matriptase, TMPRSS13. Notably, N-0920 demonstrated exceptional potency in reducing EG.5.1 JN.1 entry Calu-3 cells, representing first cellulo picomolar inhibitor EC50 300 90 pM, respectively. Additionally, molecular modeling provided insights into binding interactions between compounds their targets. This study underscores effectiveness our approach refining an scaffold enhance selectivity activity.

Язык: Английский

Процитировано

0
SARS-CoV-2 Omicron variations reveal mechanisms controlling cell entry dynamics and antibody neutralization DOI Creative Commons
Enya Qing,

Julisa Salgado,

Alexandria Wilcox

и другие.

PLoS Pathogens, Год журнала: 2024, Номер 20(12), С. e1012757 - e1012757

Опубликована: Дек. 2, 2024

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is adapting to continuous presence in humans. Transitions endemic infection patterns are associated with changes the spike (S) proteins that direct virus-cell entry. These generate antigenic drift and thereby allow virus maintenance face of prevalent human antiviral antibodies. also fine tune entry dynamics ways optimize transmission into cells. Focusing on latter aspect, we evaluated effects several S protein substitutions membrane fusion, an essential final step enveloped Membrane fusion executed by integral-membrane “S2” domains, yet found peripheral “S1” domains altered late-stage dynamics, consistent S1-S2 heterodimers cooperating throughout cell A specific H655Y change S1 stabilized a fusion-intermediate conformation delayed fusion. The sensitized viruses neutralization S2-targeting fusion-inhibitory peptides stem-helix antibodies did not interfere early fusion-activating steps; rather they targeted latest stages S2-directed novel mechanism. findings demonstrate single amino acid both reset viral entry—fusion kinetics increase sensitivity antibody neutralization. results exemplify how selective forces driving SARS-CoV-2 fitness evasion operate together shape evolution.

Язык: Английский

Процитировано

1
Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency DOI Creative Commons
Alexandre Joushomme, Antoine Désilets,

William Champagne

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 29, 2024

Abstract TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and cell entry respiratory viruses. To date, no inhibitors have been specifically developed toward this protease. In study, chemical library 65 ketobenzothiazole-based peptidomimetic molecules was screened against proteolytically active form recombinant TMPRSS13 to identify novel inhibitors. Following an initial round screening, subsequent synthesis additional derivatives supported by molecular modelling, uncovered important determinants inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards activity cellular context. Using SARS-CoV-2 pseudovirus model, we further show ability N-0430 block TMPRSS13-dependent pseudovirus. The identified insights their potency gained from study will aid development specific

Язык: Английский

Процитировано

0