Abstract
The interaction of co-stimulatory molecules on T cells with B7 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. These compounds inhibit the binding of B7.1 to both CD28 and CTLA4. Both classes of compounds appear to bind the same site, a relatively small portion of the GFCC'C" face of the N-terminal V-set domain of human B7.1, not present in the homologous B7.2 or even mouse B7.1. This site may represent a rare hot spot for small molecule antagonist design of inhibitors of cell-cell interactions, whose ligands may yield leads for the development of novel immunomodulatory medicines.
Highlights
Identification of potent, orally active, small molecule inhibitors of the extracellular binding of these co-stimulatory molecules faces a number of thermodynamic challenges common to protein-protein interactions between opposing cell surfaces
Specific small molecule inhibitors of human B7.1 were identified and characterized. These compounds inhibit the binding of B7.1 to both CD28 and CTLA4
This is especially true for interactions involving CTLA4, whose submicromolar affinity for B7.1 is unusually high for interactions between cell surface molecules [22]
Summary
Identification of potent, orally active, small molecule inhibitors of the extracellular binding of these co-stimulatory molecules faces a number of thermodynamic challenges common to protein-protein interactions between opposing cell surfaces. Both classes of compounds appear to bind the same site, a relatively small portion of the GFCCC؆ face of the N-terminal Vset domain of human B7.1, not present in the homologous B7.2 or even mouse B7.1.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
