Integrins are heterodimeric receptor molecules that function in cell adhesion and signaling, with key roles in multiple sclerosis, inflammation and cancer, and as a result are important drug targets. Currently, 3 of the 24 known human integrins have emerged as attractive targets because the effect of their inactivation has been probed by monoclonal antibodies, peptides and small molecule potential integrin inhibitors. Highly effective new antibodies and peptides targeting α4β7 have been discovered and have shown significant pre-clinical efficacy for the treatment of inflammatory bowel diseases. A case in point are the monomeric/dimeric disulfide-linked cyclic peptides PTG-100, which have recently shown major benefits in human studies. Despite this relevant finding, the characterization of the binding epitope of these new generation integrin inhibitors on the α4β7 receptor is still elusive.<br/>In this study, we report for the first time the molecular characterization of the binding interactions of clinical therapeutic disulfide-linked cyclic peptides PTG-100 against the integrin α4β7 receptor as probed by HDX/MS and computational approaches. The results of this study are of paramount importance to get a deeper insight into the involvement of α4β7 in autoimmune diseases and to guide the discovery of new chemotypes as inhibitors of this integrin receptor.

Challenging the sensitivity of HDX/MS with a large heterodimeric protein receptor: Characterization of the binding interactions of new generation integrin α4β7 inhibitors

2019 Fall National Meeting

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