ECCO Grant Study Synopsis: Simona Bertoni
Simona Bertoni, ECCO Grant Awardee
CCR6 blockade as novel therapeutic strategy against inflammatory bowel disease
© Simona Bertoni
Aim of research
CCL20 and its cognate receptor CCR6 are dysregulated in the colonic mucosa and serum of IBD patients; their genes have been identified as susceptibility genes for IBD and an anti-CCL20 neutralizing antibody has been reported to be beneficial in TNBS-induced colitis.
Our working hypothesis is that blocking the CCL20-CCR6 axis represents a novel and promising approach to IBD therapy by limiting neutrophil recruitment to the inflamed tissues and by restoring the balance of effector/regulatory T cells.
Accordingly, our aim is the preclinical validation of small-molecule CCR6 antagonists as potential drug candidates for the treatment of IBD.
Methodology/experiments that will be used
Our multidisciplinary team, composed of medicinal chemistry and pharmacology experts, proposes to consolidate and expand the encouraging preliminary in vitro and in vivo results obtained with the newly synthesised CCR6 antagonist MR-120. More potent derivatives will be in silico designed and chemically synthesised and then tested in pharmacological in vitro (chemotaxis assays) and in vivo (murine adoptive transfer colitis) studies.
Anticipated main impact
Our project will be the first to investigate the beneficial action of agents that interfere with the CCL20-CCR6 axis in a chronic model of Th1/Th17-dependent colitis. This will pave the way for the validation of a novel pharmacological target and, subsequently, the design of a fully original and innovative therapeutic approach against IBD. Moreover, by designing small-molecule non-peptidic CCR6 antagonists, our project represents an original step towards the development of orally bioavailable first-in-class drug candidates.
Months 0–8: Preparation and optimisation of new small-molecule CCR6 antagonists
Months 3–8: Identification of the most potent and tolerable CCR6 antagonist as an anti-chemotactic agent in in vitro functional assays
Months 5–12: Evaluation of MR-120 and of the novel most promising MR-120 analogue in murine adoptive transfer colitis