Vinicio Granados Soto- Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1−400 Inhibitors

5 de Diciembre del 2023

Invitamos a leer el artículo: "Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1−400 Inhibitors", en la que colaboró el Dr. Vinicio Granados-Soto, Investigador de Cinvestav Sede Sur

Autores: Enrique Aguilar-Ramírez, Valeria Reyes Pérez, Carlos A. Fajardo Hernández, Carlos D. Quezada Suaste, Mario Carreón Escalante, Verenice Merlin Lucas, Beatriz Quiroz García, Vinicio Granados Soto y José Rivera Chávez

Abstract: Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B1−400), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B1−400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a−15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b−37b). In vitro evaluation and structure−activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.

Keyword: Bioactivity, Inhibition, Molecules, Monomers, Peptides y proteins