Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal.
Adam M Spivak, Racheal A Nell, Mark Petersen, Laura Martins, Paul Sebahar, Ryan E Looper, Vicente Planelles
Author Information
Adam M Spivak: Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA adam.spivak@hsc.utah.edu.
Racheal A Nell: Division of Infectious Diseases, Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Mark Petersen: Synthetic and Medicinal Chemistry Core, Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Laura Martins: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Paul Sebahar: Synthetic and Medicinal Chemistry Core, Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Ryan E Looper: Synthetic and Medicinal Chemistry Core, Department of Chemistry, University of Utah, Salt Lake City, Utah, USA.
Vicente Planelles: Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, USA.
Antiretroviral therapy (ART) does not cure HIV-1 infection due to the persistence of proviruses in long-lived resting T cells. Strategies targeting these latently infected cells will be necessary to eradicate HIV-1 in infected individuals. Protein kinase C (PKC) activation is an effective mechanism to reactivate latent proviruses and allows for recognition and clearance of infected cells by the immune system. Several ingenol compounds, naturally occurring PKC agonists, have been described to have potent latency reversal activity. We sought to optimize this activity by synthesizing a library of novel ingenols via esterification of the C-3 hydroxyl group of the ingenol core, which itself is inactive for latency reversal. Newly synthesized ingenol derivatives were evaluated for latency reversal activity, cellular activation, and cytotoxicity alongside commercially available ingenols (ingenol-3,20-dibenzoate, ingenol 3-hexanoate, and ingenol-3-angelate) in HIV latency cell lines and resting CD4 T cells from aviremic participants. Among the synthetic ingenols that we produced, we identified several compounds that demonstrate high efficacy and represent promising leads as latency reversal agents for HIV-1 eradication.
