Background: The adoption of Antiretroviral Therapy (ART) substantially extends the life expectancy and quality of HIV-infected patients. Yet, eliminating the latent reservoirs of HIV to achieve a cure remains an unmet need. The advent of nanomedicine has revolutionized the treatment of HIV/AIDS. The present study explores a unique combination of Tenofovir (TNF) with gold nanoparticles (AuNPs) as a potential therapeutic approach to overcome several limitations of the current ART. Results: TNF-tethered AuNPs were successfully synthesized. Cell viability, genotoxicity, haemolysis, and histopathological studies confirmed the complete safety of the preparation. Most importantly, its anti-HIV1 reverse transcriptase activity was ~ 15 folds higher than the native TNF. In addition, it exhibited potent anti-HIV1 protease activity, a much sought-after target in anti-HIV1 therapeutics. Finally, the in vivo biodistribution studies validated that the AuNPs could reach many tissues/organs, serving as a secure nest for HIV and overcoming the problem of deficient drug delivery to HIV reservoirs. Conclusions: We show that the combination of TNF and AuNPs exhibits multifunctional activity, viz. anti-HIV1 and anti-HIV1 protease. These findings are being reported for the first time and highlight the prospects of developing AuNP-TNF as a novel next-generation platform to treat HIV/AIDS. Graphical

Highly active anti-retroviral therapy (HAART) is prescribed for HIV infection and, to a certain extent, limits the infection’s spread. However, it cannot completely eradicate the latent virus in remote and cellular reservoir areas, and due to the complex nature of the infection, the total eradication of HIV is difficult to achieve. Furthermore, monotherapy and multiple therapies are not of much help. Hence, there is a dire need for novel drug delivery strategies that may improve efficacy, decrease side effects, reduce dosing frequency, and improve patient adherence to therapy. Such a novel strategy could help to target the reservoir sites and eradicate HIV from different biological sanctuaries. In the current review, we have described HIV pathogenesis, the mechanism of HIV replication, and different biological reservoir sites to better understand the underlying mechanisms of HIV spread. Further, the review deliberates on the challenges faced by the current conventional drug delivery systems and introduces some novel drug delivery strategies that have been explored to overcome conventional drug delivery limitations. In addition, the review also summarizes several nanotechnology-based approaches that are being explored to resolve the challenges of HIV treatment by the virtue of delivering a variety of anti-HIV agents, either as combination therapies or by actively targeting HIV reservoir sites.

Background: Natural products have shown potent anti-HIV activity, but some of these also possess toxicity. The pharmacophoric fragments of these natural products have scope of combination with other pharmacophoric fragment and derivatization to reduce toxicity and increase the potency. Combination of natural product fragments from different classes of anti–HIV compounds may lead to a new class of potent anti–HIV agents. Objective: Design, in silico prediction of drug-likeness, ADMET properties and synthesis of pyrazol– pyridones. Evaluation of the anti–HIV–1 activity of synthesized pyrazol–pyridones. Methods: Pyrazol–pyridones were designed by combining reported anti–HIV pharmacophoric fragments. Designed molecules were synthesized after in silico prediction of drug-likeness and ADMET properties. Compounds were evaluated for activity against HIV–1VB59 and HIV–1UG070. Results: QED value of designed pyrazol–pyridones was greater than the known drug zidovudine. The designed compounds were predicted to be noncarcinogenic and nonmutagenic in nature. Seventeen novel pyrazol–pyridones were synthesized with good yield. Compound 6q and 6l showed activity with IC50 values 6.14 µM and 15.34 µM against HIV–1VB59 and 16.21 µM and 18.21 µM against HIV–1UG070, respectively. Conclusion: Compound 6q was found to be most potent among the synthesized compounds with a therapeutic index of 54.31against HIV–1VB59. This is the first report of anti–HIV–1 activity of pyrazol–pyridone class of compounds. Although the anti–HIV–1 activity of these compounds is moderate, this study opens up a new class for exploration of chemical space for anti–HIV–1 activity.