1. Novel selective proline-based peptidomimetics for human cathepsin K inhibition.
- Author
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Cardoso Prado Martins F, Dos Reis Rocho F, Bonatto V, Jatai Batista PH, Lameira J, Leitão A, and Montanari CA
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Cathepsin K antagonists & inhibitors, Cathepsin K metabolism, Peptidomimetics pharmacology, Peptidomimetics chemistry, Peptidomimetics chemical synthesis, Proline chemistry, Proline pharmacology
- 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 (pK
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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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