Abstract

Polyphenols for HIV Prophylaxis: A Journey from Discovery to Delivery

Vandana Patravale, Professor, Institute of Chemical Technology

HIV infection has become a global threat with approximately 25 million deaths till date and current estimate of about 34 million cases worldwide. Etiologically, sexual transmission (both vaginal/anal intercourse) is the most predominant mode of HIV infection with 80% prevalence and women are more susceptible to it (52% prevalence) than men. Currently, FDA has approved more than 20 anti-retroviral drugs for treatment of AIDS which act either at the replication stage or post replication stage of HIV virus. With increasing need of HIV prophylactic strategies, two molecules maraviroc (entry inhibitor) and enfuvirtide (fusion inhibitor) were recently introduced in market that inhibit HIV transmission during sexual intercourse. However, most of these drugs are reported to develop resistance and offer severe adverse effects. Thus, identification of safe and effective drug candidates that can prevent HIV transmission via unprotected sexual intercourse preferably at the entry stage (gp120-CD4 binding stages) of HIV life cycle forms a strong rationale. Conformational understanding of CD4 receptor revealed that gp120-CD4 binding inhibition can be achieved by identifying inhibitors that can bind to the hydrophobic Phe43 cavity in CD4 receptor. With this understanding, a suitable class of naturally occurring polyphenols was subjected to in silico screening (molecular docking and dynamics simulation studies) using homology model of gp12-CD4 binding. Amongst the tested polyphenols, punicalagin exhibited superior gp120-CD4 binding affinity due to its stable hydrophobic interactions with residues Asp368 and Trp427at deeper site in Phe43 cavity and was considered as a lead. Further, this hypothesis was confirmed by in vitro anti-HIV activity wherein the lead polyphenol exhibited similar inhibitory concentration (IC50=0.237µM) to that of the marketed chemical entity tenofovir disoproxil fumarate (IC50=0.239 µM). With this proof of concept, novel HIV prophylactic natural nanomicrobicide was developed and optimized wherein the extract of P. granatum (pomegranate, a rich natural source of punicalagin) was fabricated in nanocarrier gel formulation for rectal and vaginal application. The P. granatum extract loaded nanomicrobicide exhibited 40 times higher anti HIV activity as compared to P. granatum extract and tenofovir disoproxil fumarate. Further, it showed mild but acceptable irritation score when tested in rabbit for consecutive for 14 days application. Thus, the novel natural nanomicrobicide ensured enhanced efficacy and acceptable safety proving the potential of polyphenols as gp120-CD4 binding inhibitors for prevention of HIV transmission.