Principal Investigator/Program Director (Last, First, Middle): Chaiken, Irwin M / Smith, AmOS B. DESCRIPTION: The Overarching Aim of the Small Molecule Synthesis Thrust for years 12-16 is to discover high potency inhibitors (antagonists) of the HIV-1 viral attachment to the host cell. Two parallel approaches will be taken. The first will entail a screening program to discover perspective new scaffolds for the development of small molecule inhibitors of HIV-1 cell fusion. The library collections and databases for this screen include the Accelys' library comprised of ca. 500,000 small organic compounds, now the property of the Penn Center for Molecular Discovery and the Zinc database. The second approach will involve a series of Specific Aims exploiting iterative structural-based design, synthesis and biological evaluation, carried out in conjunction with members of the Program Project team. These aims include: (1) The development of a strategy for the design and synthesis of small molecule HIV-1 fusion inhibitors by: (a) Exploiting our highly successful, covalent modification/fragment-based SAR/X-ray crystallographic studies, utilizing CD4 mutants and scorpion toxin miniproteins to define the structural characteristics required for binding at the Phe-43 pocket and vestibule of gp120 in the CD4 bound state; and (b) Identifying the structural elements that can occupy the water-filled channel, extending out of the Phe-43 pocket in the gp120-CD4 complex, exploiting both structural-based design tactics and the in situ [3+2] dipolar cycloaddition "click-chemistry" developed by Sharpless; (2) Devise and refine SAR maps of known compounds such as NBD-556 and BMS-806 that either promote or inhibit, respectively, the gp120-CD4-coreceptor entry pathway, with the aim of converting these small molecules into inhibitors of the gp120-CD4 attachment process; (3) Derivatize and conjugate the small molecule NBD-556 and the more potent analogues thereof, discovered by the PO-1 team to be potent CD4 mimetics, with known allosteric inhibitors, such as BMS-806 and 12p1, to convert the NBD-556 small molecule agonist to an antagonist, and (5) Transform the most potent miniprotein and peptide aptamer lead compounds to structurally and functionally congruent antagonists, exploiting a variety of scaffolds, including the Smith-Hirschmann polypyrrolinone. Taken together, the efforts of the Small Molecule Synthesis Thrust (Project 3) in conjunction with other members of the Program Project team will lead to the continued refinement and enhancement of our understanding at the molecular level of the viral-host fusion machinery, and in turn to the development of potentially useful small molecule inhibitors (antagonists), as an effective intervention in the treatment of the AIDS pandemic.