Novel selective proline-based peptidomimetics for human cathepsin K inhibition

Author(s)

Martins, Felipe Cardoso Prado ; Rocho, Fernanda dos Reis ; Bonatto, Vinicius ; Batista, Pedro Henrique Jatai ; Lameira, Jeronimo ; Leita, Andrei ; Montanari, Carlos A.

• Document type: Journal article
• Source: Bioorganic & Medicinal Chemistry Letters; v. 110, p. 7-pg., 2024-07-12.

Abstract

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)

• FAPESP's process: 19/06271-2 - Synthesis of novel anti-Trypanosoma cruzi agents
• Grantee: Felipe Cardoso Prado Martins
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/01393-5 - On the development of SARS-CoV-2 3CL Mpro Coronavirus main protease inhibitors as antiviral agents
• Grantee: Carlos Alberto Montanari
• Support Opportunities: Regular Research Grants