The road to Insurmountability: Novel avenues to better target CC Chemokine Receptors

Ortiz Zacarías, N.V. (2019)

Doctoral Thesis

This thesis explores different avenues to develop insurmountable antagonists for CC Chemokine Receptors, such as CCR1, CCR2 and CCR5. These receptors, which belong to the large family of G protein-coupled receptors (GPCRs), are implicated in a variety of inflammatory and immune diseases, including atherosclerosis, rheumatoid arthritis and cancer. Thus, numerous drug candidates have been developed over the years to target them. Despite promising preclinical data, most of these candidates have failed in clinical trials due to lack of efficacy, making necessary the development of novel tools and concepts to better study and target these receptors. Thus, throughout this thesis we have explored different mechanisms to achieve insurmountable inhibition, which include intracellular allosteric modulation, covalent inhibition and long residence time. Moreover, the crystal structure presented in this thesis provides a new template for the rational design of future antagonists. Finally, with the identification of several selective or multitarget intracellular ligands for CCR1, CCR2 and CCR5, we are expanding the toolbox to further modulate chemokine receptors. Overall, the results of this thesis may contribute to the development of novel chemokine receptor antagonists, and GPCRs in general, with improved in vivo efficacy.

• G protein coupled receptors
• Allosteric modulation
• Insurmountable antagonism
• Intracellular ligands
• Atherosclerosis
• Covalent ligands
• Multitarget ligands
• Crystal structure

• All authors: Ortiz Zacarías, N.V.
• Supervisor: IJzerman, A.; Heitman, L.
• Committee: Irth, H.; Bouwstra, J.; Rosenkilde, M.; Junker, A.; Wijtmans, M.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
• Date: 2019-12-04