According to the World Health Organization, HIV currently effects approximately 35 million people and accounts for the deaths of 1.5 million individuals annually. Alternative strategies for preventing HIV transmission are necessary in the absence of a vaccine, especially in resource-limited regions where antiretroviral treatment and current preventative measures may be unavailable or are culturally unaccepted. Anionic polymer microbicides have been in development and have seen some levels of success, but no potent HIV microbicide is commercially available. Computationally optimizing the safety, biocompatibility, and efficacy of microbicide treatment options will allow for this treatment’s commercialization. Several potent anti-HIV anionic polymers were recently developed. The polymer with the best inhibitory properties, poly(4,4′-stilbenedicarboxylate-alt-maleic acid (DCSti-alt-MA), displayed IC50 values of 37 nM, 5 nM, 37 nM, and 12 nM for HIV92UG037, HIVIIIb, HIVJR-CSF, and HIVBaL, respectively (J. Med. Chem., 2014 Aug 14;57(15):6354-63). Mechanistic study and further optimization of these compounds is necessary to translate these compounds to the clinic and protect against a broad range of HIV strains. To explore and maximize the effectiveness of these polymers, various n-length polymers were energy minimized using the AM1 semi-empirical method. To explore binding affinity across a broad range of polymeric lengths, extensive molecular docking studies were conducted to localize potential HIV binding regions. Due to the positive charge density of the V3 loop region, additional docking was focused exclusively on this region. Poor resolution of this region in crystal structures necessitated the use of homology modeling to create representative structures for each strain of HIV (HIV92UG037, HIVIIIb, HIVJR-CSF, and HIVBaL). Preliminary data suggest two binding modes that correlate to sequence identities between these sets of strains. Future work aims to use structure-guided drug design to generate broadly protective compounds from the lead polymer in addition to microscopy and in vivo studies.

Computational insights into the optimization of anti-HIV alternating copolymers

251st National Meeting (2016)

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