BIFI TALK: Andrea Ilari, Istituto di Biologia e Patologia Molecolari, IBPM of CNR c/o Dip. Scienze Biochimiche Università Sapienza,Roma
BIFI TALK: Andrea Ilari, Istituto di Biologia e Patologia Molecolari, IBPM of CNR c/o Dip. Scienze Biochimiche Università Sapienza, P.le Aldo Moro 5, 00185 Roma
Título: Exploiting a Druggable E2 Ubiquitin Conjugating Enzyme and an E3 Ligase for PROTAC-Mediated Degradation of Trypanothione Reductase in Leishmania
Abstract
Leishmaniasis is a neglected tropical disease affecting up to one million people annually according to the World Health Organization. Visceral leishmaniasis, caused by Leishmania infantum, is the most severe form of the disease and can be fatal if left untreated. Current therapies are limited by toxicity, variable efficacy, lengthy treatment regimens, and the emergence of drug resistance [1].
The parasite survives the oxidative burst generated by host macrophages through a unique trypanothione-based redox system, whose central enzyme, trypanothione reductase (TR), maintains trypanothione in its reduced state. Owing to its essential role in parasite survival, absence in humans, and favorable druggability profile, TR has long been considered an attractive therapeutic target. However, despite decades of research, no TR inhibitors have advanced to clinical development, mainly because of insufficient efficacy and safety concerns [2].
Targeted protein degradation has recently emerged as an alternative therapeutic strategy capable of eliminating, rather than inhibiting, disease-relevant proteins. PROteolysis TArgeting Chimeras (PROTACs) are bifunctional molecules that induce ubiquitination and subsequent proteasomal degradation of a target protein by recruiting components of the ubiquitin–proteasome system (UPS) [3]. As first step, we developed TR-targeting PROTACs designed to recruit a putative Leishmania E3 ligase, but their activity was modest and the recruited E3 remains poorly characterized. To overcome these limitations, we propose an innovative E2-recruiting PROTAC strategy that bypasses the requirement for a defined E3 ligase. As a first step, we structurally and functionally characterized a Leishmania major ubiquitin-conjugating enzyme (E2). Crystallographic fragment screening identified potential ligandable sites on the enzyme, while DeepFrag-guided fragment expansion and AutoDock Vina docking were employed to generate and prioritize E2-binding chemotypes. Together, these studies establish the molecular framework for the rational development of E2-recruiting PROTACs targeting TR and open new opportunities for exploiting the ubiquitin–proteasome system in antileishmanial drug discovery [4].
References
[1] S. Pradhan, R. A. Schwartz, A. Patil, S. Grabbe, and M. Goldust, Clin Exp Dermatol, 2022, 47, 516.
[2] T. Battista, G. Colotti, A. Ilari, and A. Fiorillo, Molecules, 2020. 25, 1924.
[3] S. Gu, D. Cui, X. Chen, X. Xiong, and Y. Zhao, BioEssays, 2018, 40, e1700247.
[4] C. Exertier, L. Antonelli, A. Liuzzi, M. Ruffa, V. Brufani, G. Colotti, A. Fiorillo, A. Ilari; ACS Omega 2026; https://doi.org/10.1021/
