Development of HIV-1 Cell Entry Inhibitors

摘要

Protein-protein interactions define critical targets for drug development against different diseases including AIDS. Until now, the clinical inhibition of protein-protein interactions and signaling has been accomplished with the use of antibodies or soluble versions of receptor molecules. Small molecule inhibitors of protein/protein interactions have been extremely difficult to develop; either the necessary potency has not been achieved, the expected biological effect has not been obtained or unwanted effects have been observed. We have shown that a rigorous thermodynamic approach that combines differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC) provides a unique platform for the identification and optimization of small molecular weight inhibitors of protein-protein interactions. In particular, this approach has been very successful in the optimization of gpl20/CD4 inhibitors.