2. Academic Validation
  3. A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties

  • Eur J Med Chem. 2024 Sep 5:275:116567. doi: 10.1016/j.ejmech.2024.116567.
Antonio Laghezza 1,  Carmen Cerchia 2,  Massimo Genovese 3,  Roberta Montanari 4,  Davide Capelli 4,  Judith Wackerlig 5,  Stefan Simic 5,  Emanuele Falbo 2,  Lucia Pecora 3,  Rosalba Leuci 1,  Leonardo Brunetti 1,  Luca Piemontese 1,  Paolo Tortorella 1,  Abanish Biswas 6,  Ravi Pratap Singh 6,  Suhas Tambe 7,  C A Sudeep 8,  Ashok Kumar Pattnaik 6,  Venkatesan Jayaprakash 6,  Paolo Paoli 3,  Antonio Lavecchia 9,  Fulvio Loiodice 10
Affiliations

Affiliations

  • 1 Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125, Bari, Italy.
  • 2 Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", via D. Montesano 49, 80131, Napoli, Italy.
  • 3 Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy.
  • 4 Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Montelibretti, 00015 Monterotondo Stazione, Roma, Italy.
  • 5 Department of Pharmaceutical Sciences, Faculty of Life Sciences, University of Vienna, 1090, Vienna, Austria.
  • 6 Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
  • 7 Adgyl Lifescience Private Ltd., Bengaluru, 560058, India.
  • 8 Bioanalytical Section, Eurofins Advinus Biopharma Services India Pvt Ltd., Bengaluru, 560058, India.
  • 9 Dipartimento di Farmacia, "Drug Discovery" Laboratory, Università degli Studi di Napoli "Federico II", via D. Montesano 49, 80131, Napoli, Italy. Electronic address: antonio.lavecchia@unina.it.
  • 10 Dipartimento Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via Orabona 4, 70125, Bari, Italy. Electronic address: fulvio.loiodice@uniba.it.
PMID: 38865743 DOI: 10.1016/j.ejmech.2024.116567
Abstract

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

Keywords

Anti-steatotic effects; Crystallographic studies; Docking experiments; Glucose uptake; MPC inhibition; PPAR dual-agonist.

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