Design, synthesis and biological evaluation of novel intracellular modulators attenuating CCR5 signaling

Promovendus/a: Margaux Billen

Promotor(en): Prof. dr. Peter Verwilst, Prof. dr. Scott Webster, Prof. dr. Dominique Schols

CCR5 is a receptor involved in several serious diseases, including HIV, cancer, and immune disorders. Because of its role in these conditions, it’s an important target for developing new treatments. This research focuses on designing small molecules that can block CCR5 from inside the cell, aiming to reduce harmful signaling caused by its overactivation.

We started by identifying a promising compound, IV-1, through computer-based screening. This molecule showed good potential to inhibit CCR5 activity. From there, we created and tested 90 related compounds to improve their effectiveness, selectivity (so they target CCR5 and not similar receptors like CCR2), and solubility (so they work well in biological systems).

Two standout compounds were IV-3ad and V-2a. IV-3ad was highly effective and selective but had poor solubility. V-2a was very soluble and still active, though less selective. These compounds are promising starting points for further development.

Computer simulations and lab tests confirmed that these molecules bind to a specific site inside CCR5, interfering with its normal function. We also tested their effects on cancer cells and found that they could influence cell growth and movement, suggesting potential for cancer therapy.

In conclusion, this work introduces a new class of CCR5 blockers that could help in treating diseases linked to this receptor. Future research will focus on improving these compounds and exploring their full therapeutic potential.