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Open AccessArticle

New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin

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Departamento de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politecnico Nacional, Av. Wilfrido Massieu S/N, Col. Unidad Profesional Adolfo López Mateos, Zacatenco, Ciudad de Mexico 07738, Mexico
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Departamento de Biofísica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prolongación de Carpio y Plan de Ayala S/N, Col. Santo Tomás, CP. Ciudad de Mexico 11340, Mexico
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Departamento de Microbiologia e Immunologia, Facultad de Medicina Veterinaria Y Zootecnia, Universidad Nacional Autonoma de Mexico, Av. Universidad #3000, Delegacion Coyoacan, Col. Ciudad Universitaria, Ciudad de Mexico 04510, Mexico
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Centro de Investigación en Biotecnología Aplicada CIBA, Instituto Politécnico Nacional, Carretera Estatal, Tecuexcomac-Tepetitla, Km 1.5, CP. Tlaxcala 90700, Mexico
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Author to whom correspondence should be addressed.
Academic Editor: Florenci V. González
Molecules 2019, 24(21), 3887; https://doi.org/10.3390/molecules24213887
Received: 16 September 2019 / Revised: 23 October 2019 / Accepted: 23 October 2019 / Published: 28 October 2019
(This article belongs to the Special Issue Design and Synthesis of Protease Inhibitors)
Protease inhibition has led to treating many diseases and has been successful in producing many commercial drugs by pharmaceutical companies. Among many proteases, serine protease has been attractive in treating metabolic disorder diabetes mellitus (DM). Gliptins have been proven to inhibit dipeptidyl peptidase-4 (DPP4), a serine protease, and are an emerging therapeutic drug target to reduce blood glucose levels, but until now there is no natural cyclic peptide proven to inhibit serine protease DPP4. This study demonstrates the potential mechanism of natural cyclic peptide oxytocin (OXT) as a DPP4 inhibitor. To achieve this, initially, activity atlas and field-based models of DPP4 inhibitors were utilized to predict the possible features of positive and negative electrostatic, hydrophobic, and activity shapes of DPP4 inhibition. Oxytocin binding mode, flexibility, and interacting residues were studied using molecular docking simulations studies. 3D-RISM calculations studies revealed that the stability of water molecules at the binding site are favorable. Finally, an experimental study using fluorescence assay revealed OXT inhibits DPP4 in a concentration-dependent manner in a significant way (p < 0.05) and possess IC50 of 110.7 nM. These new findings significantly expand the pharmaceutical application of cyclic peptides, and in specific OXT, and implicate further optimization of OXT inhibition capacity to understand the effect of DPP4 inhibition. This work highlights the development of natural cyclic peptides as future therapeutic peptides to reduce glucose levels and treat diabetes mellitus. View Full-Text
Keywords: diabetes treatment; cyclic peptides; oxytocin; dipeptidyl peptidase-4 inhibition; peptide therapeutics diabetes treatment; cyclic peptides; oxytocin; dipeptidyl peptidase-4 inhibition; peptide therapeutics
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MDPI and ACS Style

Chittepu, V.C.S.R.; Kalhotra, P.; Osorio-Gallardo, T.; Jiménez-Martínez, C.; Robles-de la Torre, R.R.; Gallardo-Velazquez, T.; Osorio-Revilla, G. New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin. Molecules 2019, 24, 3887.

AMA Style

Chittepu VCSR, Kalhotra P, Osorio-Gallardo T, Jiménez-Martínez C, Robles-de la Torre RR, Gallardo-Velazquez T, Osorio-Revilla G. New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin. Molecules. 2019; 24(21):3887.

Chicago/Turabian Style

Chittepu, Veera C.S.R.; Kalhotra, Poonam; Osorio-Gallardo, Tzayhri; Jiménez-Martínez, Cristian; Robles-de la Torre, Raúl R.; Gallardo-Velazquez, Tzayhri; Osorio-Revilla, Guillermo. 2019. "New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin" Molecules 24, no. 21: 3887.

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