Procept's objective in the NCDDG Program is to transform basic biological and structural information into unique and practical small-molecule drug leads for AIDS therapy. We expect to do this, in close collaboration with Dana-Farber and Harvard, by using the detailed three-dimensional structural information obtained from crystallographic studies of CD4. Two strategies will be used for producing small molecules which block HIV entry into cells by interfering with CD4/gp120 binding: (A) design and synthesis of small molecules targeted to bind to CD4 (negative image approach) in a cleft known to affect gp120 association, and (B) design and synthesis of modified oligopeptide and peptidomimetics that structurally resemble the binding region of CD4 (positive image); these will act by binding to gp120. Strategy A will employ the DOCK program to first create a negative image or template of a key CD4 cleft near the binding site and to then search extensive, small molecule structural databases for compounds likely to bind CD4. Based on the degree of fit to the template, the top compounds will be selected for evaluation in a series of assays, and those molecules with the desired profile will be optimized for binding affinity and therapeutic properties. Lead potency will be optimized by interactive cycles of computer-based inhibitor design, synthesis, bioevaluation, receptor-fit analysis and re-design. Use of CD4-inhibitor co-crystal structural data is a critical component of the design cycle to assure rapid convergence on high-inhibitors, although significant progress via more classical methods can also be expected. Strategy B targets two sets of inhibitors: (1) cyclically constrained peptide analogs of the CD4 C'C"""""""" ridge that retain correct torsion angles and side chain positioning, and (2) non-peptide rigid mimics of beta-strand segment 43-46 of the C'C"""""""" ridge. High resolution NMR will be crucial to each of these approaches, and initial progress has already been achieved in both cases. Viable leads from all approaches must pass many tests and exhibit: potent receptors binding affinity (cellular and ELISA); specificity (immunosuppression does not accompany inhibition of cellular gp120 binding), anti-HIV activity (lab strains and clinical isolates), low cytotoxicity (multiple cell lines). Taken together, our structure-based design strategies, should not only cytotoxicity (multiple cell lines). Taken together, our structure-based design strategies, should not only yield novel leads for treating AIDs, but should also advance the methods of rational drug design.
Showing the most recent 10 out of 13 publications
