Prodrugs of PKC modulators show enhanced HIV latency reversal and an expanded therapeutic window

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 20; pp. 10688 - 10698
• Main Authors: Sloane, Jack L., Benner, Nancy L., Keenan, Katherine N., Zang, Xiaoyu, Soliman, Mohamed S. A., Wu, Xiaomeng, Dimapasoc, Melanie, Chun, Tae-Wook, Marsden, Matthew D., Zack, Jerome A., Wender, Paul A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-05-2020
• Subjects: Antiretroviral agents; Antiretroviral therapy; Biological Sciences; Biomarkers; CD69 antigen; Chemical compounds; Developmental stages; Drug delivery systems; Drugs; Esters; HIV; Human immunodeficiency virus; Kinases; Latency; Latent infection; Modulators; Pandemics; Physical Sciences; Prodrugs; Protein kinase C; Side effects; Therapeutic applications; Toxicity; Viruses; HIV/AIDS; bryostatin; prostratin; ingenol; protein kinase C
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1919408117

AIDS is a pandemic disease caused by HIV that affects 37 million people worldwide. Current antiretroviral therapy slows disease progression but does not eliminate latently infected cells, which resupply active virus, thus necessitating lifelong treatment with associated compliance, cost, and chemoexposure issues. Latencyreversing agents (LRAs) activate these cells, allowing for their potential clearance, thus presenting a strategy to eradicate the infection. Protein kinase C (PKC) modulators—including prostratin, ingenol esters, bryostatin, and their analogs—are potent LRAs in various stages of development for several clinical indications. While LRAs are promising, a major challenge associated with their clinical use is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. Here we describe a strategy to address this problem based on LRA prodrugs, designed for controllable release of the active LRA after a single injection. As intended, these prodrugs exhibit comparable or superior in vitro activity relative to the parent compounds. Selected compounds induced higher in vivo expression of CD69, an activation biomarker, and, by releasing free agent over time, significantly improved tolerability when compared to the parent LRAs. More generally, selected prodrugs of PKC modulators avoid the bolus toxicities of the parent drug and exhibit greater efficacy and expanded tolerability, thereby addressing a longstanding objective for many clinical applications.