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Novel selective proline-based peptidomimetics for human cathepsin K inhibition

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Autor(es):
Martins, Felipe Cardoso Prado ; Rocho, Fernanda dos Reis ; Bonatto, Vinicius ; Batista, Pedro Henrique Jatai ; Lameira, Jeronimo ; Leita, Andrei ; Montanari, Carlos A.
Número total de Autores: 7
Tipo de documento: Artigo Científico
Fonte: Bioorganic & Medicinal Chemistry Letters; v. 110, p. 7-pg., 2024-07-12.
Resumo

Human cathepsin K (CatK) stands out as a promising target for the treatment of osteoporosis, considering its role in degrading the bone matrix. Given the small and shallow S2 subsite of CatK and considering its preference for proline or hydroxyproline, we now propose the rigidification of the leucine fragment found at the P2 position in a dipeptidyl-based inhibitor, generating rigid proline-based analogs. Accordingly, with these new proline-based peptidomimetics inhibitors, we selectively inhibited CatK against other human cathepsins (B, L and S). Among these new ligands, the most active one exhibited a high affinity (p K i = 7.3 - 50.1 nM) for CatK and no inhibition over the other cathepsins. This specific inhibitor harbors two novel substituents never employed in other CatK inhibitors: the trifluoromethylpyrazole and the 4-methylproline at P3 and P2 positions. These results broaden and advance the path toward new potent and selective inhibitors for CatK. (AU)

Processo FAPESP: 19/06271-2 - Síntese de novos agentes anti-Trypanosoma cruzi
Beneficiário:Felipe Cardoso Prado Martins
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 22/01393-5 - Sobre o desenvolvimento de inibidores da principal protease do Coronavírus SARS-CoV-2 3CL Mpro como agentes antivirais
Beneficiário:Carlos Alberto Montanari
Modalidade de apoio: Auxílio à Pesquisa - Regular