Dataset Information

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.

ABSTRACT: Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M^pro), its moderate activity in M^pro inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin's efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Golden Syrian hamsters with sulfonated Calpeptin at a dose of 1 mg/kg body weight reduces the viral load in the trachea. Despite a higher risk of side effects, an intrinsic advantage in targeting host proteins is their mutational stability in contrast to highly mutable viral targets. Here we show that the inhibition of cathepsins, a protein family of the host organism, by calpeptin is a promising approach for the treatment of SARS-CoV-2 and potentially other viral infections.

SUBMITTER: Reinke PYA

PROVIDER: S-EPMC10584882 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.

Reinke Patrick Y A PYA de Souza Edmarcia Elisa EE Günther Sebastian S Falke Sven S Lieske Julia J Ewert Wiebke W Loboda Jure J Herrmann Alexander A Rahmani Mashhour Aida A Karničar Katarina K Usenik Aleksandra A Lindič Nataša N Sekirnik Andreja A Botosso Viviane Fongaro VF Santelli Gláucia Maria Machado GMM Kapronezai Josana J de Araújo Marcelo Valdemir MV Silva-Pereira Taiana Tainá TT Filho Antônio Francisco de Souza AFS Tavares Mariana Silva MS Flórez-Álvarez Lizdany L de Oliveira Danielle Bruna Leal DBL Durigon Edison Luiz EL Giaretta Paula Roberta PR Heinemann Marcos Bryan MB Hauser Maurice M Seychell Brandon B Böhler Hendrik H Rut Wioletta W Drag Marcin M Beck Tobias T Cox Russell R Chapman Henry N HN Betzel Christian C Brehm Wolfgang W Hinrichs Winfried W Ebert Gregor G Latham Sharissa L SL Guimarães Ana Marcia de Sá AMS Turk Dusan D Wrenger Carsten C Meents Alke A

Communications biology 20231018 1

Several drug screening campaigns identified Calpeptin as a drug candidate against SARS-CoV-2. Initially reported to target the viral main protease (M<sup>pro</sup>), its moderate activity in M<sup>pro</sup> inhibition assays hints at a second target. Indeed, we show that Calpeptin is an extremely potent cysteine cathepsin inhibitor, a finding additionally supported by X-ray crystallography. Cell infection assays proved Calpeptin's efficacy against SARS-CoV-2. Treatment of SARS-CoV-2-infected Gol ...[more]

PMID: 37853179

Similar Datasets

Project description:PurposeA therapeutic agent that targets both viral replication and the hyper-reactive immune response would offer a highly desirable treatment for severe acute respiratory syndrome corona virus 2 (SARS-CoV-2, coronavirus disease 2019, COVID-19) management. Emvododstat (PTC299; 4-chlorophenyl 6-chloro-1-[4-methoxyphenyl]-1,3, 4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxylate) was found to be a potent inhibitor of immunomodulatory and inflammation-related processes by inhibition of dihydroorotate dehydrogenase to reduce the severity of SARS-CoV-2 infections This drug interaction study was performed to determine if emvododstat was an inhibitor of CYP2D6.MethodsPotential drug-drug interactions between emvododstat and a CYP2D6 probe substrate (dextromethorphan) were investigated by measuring plasma dextromethorphan and metabolite (dextrorphan) concentrations before and after emvododstat administration. On day 1, 18 healthy subjects received an oral dose of 30 mg dextromethorphan followed by a 4-day washout period. On day 5, subjects received an oral dose of 250 mg emvododstat with food. Two hours later, 30 mg dextromethorphan was administered.ResultsWhen given with emvododstat, plasma dextromethorphan concentrations increased substantially, while metabolite levels (dextrorphan) remained essentially the same. Maximum plasma dextromethorphan concentration (Cmax) increased from 2006 to 5847 pg/mL. Dextromethorphan exposure (AUC) increased from 18,829 to 157,400 h·pg/mL for AUC0-last and from 21,585 to 362,107 h·pg/mL for AUC0-inf following administration of emvododstat. When dextromethorphan parameters were compared before and after emvododstat, least squares mean ratios (90% confidence interval) were found to be 2.9 (2.2, 3.8), 8.4 (6.1, 11.5), and 14.9 (10.0, 22.1) for Cmax, AUC0-last, and AUC0-inf, respectively.ConclusionEmvododstat appears to be a strong CYP2D6 inhibitor. No drug-related treatment emergent adverse effects (TEAEs) were considered to be severe or serious.Trial registrationEudraCT 2021-004626-29, 11 May 2021.

Dataset Information

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.

Publications

Calpeptin is a potent cathepsin inhibitor and drug candidate for SARS-CoV-2 infections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets