Abstract
Addressing antimicrobial resistance by innovative drug design targeting protein degradation
Results achieved
The project has established a multidisciplinary platform for the rational design, synthesis and biological evaluation of bacterial PROTACs (bPROTACs) targeting Gram-negative pathogens. Computational studies identified key structural determinants governing ternary complex formation and highlighted the critical role of linker composition in stabilizing ClpXP:bPROTAC:target assemblies, enabling the selection of the most promising candidates for experimental validation. In parallel, optimized synthetic routes, including the implementation of a solid-phase strategy, significantly improved compound purity and reproducibility, allowing the preparation of modular building blocks targeting both DHFR and LasR. Biological studies established robust protocols for recombinant protein production and binding assays, while also revealing bacterial uptake as a major limitation for the first-generation compounds, providing valuable insights for the design of next-generation analogues. Finally, the project generated new methodologies for evaluating bacterial targeted protein degradation and produced the first original results on HomoBacPROTACs, laying the foundations for future antibacterial protein degrader development. Abstract: AntiMicrobial Resistance (AMR) represents one of the most challenging global Public Health issue, accounting for at least 1.2 M deaths worldwide, fuelled by a drying pipeline of antibiotics R&D; and the rapid diffusion of multidrug-resistant isolates. Meanwhile, the discovery of heterobifunctional molecules, able to recruit the eucaryotic proteasome to trigger the specific degradation of virtually any protein of interest (POI), has started a new era for medicinal chemistry. Such molecules, named PROTACs (PROteolysis-TArgeting Chimeras), already reached the stage of clinical development (e. g. androgen and estrogen receptor-targeting). Recent research demonstrated that protein targeted degradation can be achieved in Gram-positive bacteria, through the design of molecules bearing on one side a ligand of the POI and on the other a degron signal recognized by the ClpCP degradation machinery. Our project aims to reposition the PROTAC approach for the design of innovative and groundbreaking first-in-class compounds targeting protein degradation in Gram-negative bacteria, and therefore to establish proof of concept and feasibility of this promising approach, representing an interesting alternative to classical antibiotics.Project details
Unibo Team Leader: Andrea Milelli
Unibo involved Department/s:
Dipartimento di Farmacia e Biotecnologie
Dipartimento di Scienze per la Qualità della Vita
Coordinator:
Università degli Studi di TORINO(Italy)
Total Unibo Contribution: Euro (EUR) 70.570,00
Project Duration in months: 24
Start Date:
30/11/2023
End Date:
28/02/2026
