2. Academic Validation
  3. Novel selective proline-based peptidomimetics for human cathepsin K inhibition

Novel selective proline-based peptidomimetics for human cathepsin K inhibition

  • Bioorg Med Chem Lett. 2024 Sep 15:110:129887. doi: 10.1016/j.bmcl.2024.129887.
Felipe Cardoso Prado Martins 1,  Fernanda Dos Reis Rocho 1,  Vinícius Bonatto 1,  Pedro Henrique Jatai Batista 1,  Jerônimo Lameira 2,  Andrei Leitão 1,  Carlos A Montanari 3
Affiliations

Affiliations

  • 1 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590 São Carlos/SP, Brazil.
  • 2 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590 São Carlos/SP, Brazil; Institute of Biological Science, Federal University of Pará, Rua Augusto Correa S/N, Belém, PA, Brazil.
  • 3 Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590 São Carlos/SP, Brazil. Electronic address: Carlos.Montanari@usp.br.
PMID: 39002936 DOI: 10.1016/j.bmcl.2024.129887
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 (pKi = 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.

Keywords

Cysteine protease; Human cathepsin K; Nitrile inhibitors; Rigid analog.

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