The Rational Design, Synthesis, And Biological Evaluation Of Small Molecule Cd4 Mimetic Families For Hiv-1 Viral Entry Inhibition
Small Molecule Synthesis
Small Molecule Therapeutics
Despite extensive research and a number of approved therapeutic approaches, a preventative and curative treatment for HIV infection and AIDS still remains a prominent global health need. A strategy employed for more than a decade within the Smith Laboratory, in collaboration with multiple collaborators within a NIH-funded P01 project (P01 AI 150471), has been to target the HIV-1 viral envelope as a means to prevent HIV-1 viral entry and subsequent infection. The small molecules developed in the Smith Laboratory, based on initial findings by Debnath and coworkers, act as mimics of the natural immune system receptor CD4, which binds within the viral envelope’s gp120 glycoprotein subunit. Binding of CD4 and gp120 elicits a cascade of events that ultimately results in viral entry into host cells. The small molecule CD4 mimetics developed by the Smith laboratory are able to bind within the gp120-CD4 binding pocket, and thus prevent the events that would result in viral entry. Through extensive SAR work, a lead CD4 mimetic compound BNM-III-170 containing an indanone core has been identified with a micromolar potency value of inhibition (IC50 JR-FL: 13.9 µM); however, for a CD4 mimetic to be seriously considered for clinical consideration, a 10- to 100-fold increase in potency is required. It was hypothesized that the potency of these CD4 mimetics could be improved upon both by maintaining the hydrogen-bonding interactions with highly conserved amino acid residues that lead CD4 mimetic BNM-III-170 engages with in the gp120 binding cavity but also by branching into new chemical space to establish hydrogen-bonding interactions with other additional, conserved amino acid residues. With the aid of computational modeling, three different families of CD4 mimetics were rationally designed, synthesized, and evaluated in vitro for HIV-1 inhibitory activity. These families explore bioisoteric replacement of the lead’s guanidinium group at the 2-position of the indanone (Chapter 2), a 5,7-disubstituted pattern around the lead BNM-III-170 indanone core (Chapter 3), and incorporation of heterocyclic amines at C(5) of BNM-III-170.