The integrin αVβ3 receptor has been implicated in several important diseases and disease processes, including osteoporosis, sickle cell disease vaso-occlusion, tumor angiogenesis, proteinuric renal disease, and herpes virus infection, but no αVβ3 antagonists are approved for human therapy. One possible limitation of current small-molecule antagonists is their ability to induce a major conformational change in the receptor that induces it to adopt a high-affinity ligand-binding state. In response, we used structural inferences from a pure peptide antagonist to design the small-molecule pure antagonists TDI-4161 and TDI-3761. Both compounds inhibit αVβ3-mediated cell adhesion to αVβ3 ligands, but do not induce the conformational change as judged by antibody binding, electron microscopy, X-ray crystallography, and receptor priming studies. Both compounds have the favorable property of inhibiting bone resorption in vitro, supporting their potential value in treating osteoporosis. Neither, however, has the unfavorable property of the αVβ3 antagonist cilengitide of paradoxically enhancing aortic sprout angiogenesis at concentrations below its IC<sub>50</sub>, which correlates with cilengitide’s enhancement of tumor growth in vivo. We are currently planning preclinical studies to assess whether these or related compounds have potential therapeutic advantages over current small molecule aVβ3 antagonists that act as partial agonists by inducing the conformational change.

Structure-guided design of pure αVβ3 antagonists

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.