Effect of Mimetic CDK9 Inhibitors on HIV-1-Activated Transcription

Abstract

Potent antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic manageable disease; however drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study we utilized a combination of structure based analysis of Cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket which showed the most stable binding site (Cavity 1) using in silico analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using in silico searches of a chemical library, followed by cell based biological assays. Using these methods we obtained the first generation mimetic drugs and tested these compounds on HIV-1 LTR activated transcription. Using biological assays followed by similar in silico analysis to find a 2nd generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the 2nd generation mimetic against various viral isolates, and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2-/-γc-/- with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using in silico analysis.

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

“…We used U1 cells treated with cART for 5 days and subsequently treated with two different transcription inhibitors. We have previously shown that a mimetic of Tat (F07 number 13) and an ATP analog blocking CDK9 (CR8 number 13) can inhibit viral transcription (46). Both F07 number 13 and CR8 number 13 was used to treat U1 cells, and exosomes were isolated after 24 and 72 h using nanoparticles.…”

CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses

“…We have developed chemical inhibitors that target host kinases as antiviral agents, which prevent the replication of several viruses, including the hepatitis C virus, dengue virus, and Sindbis virus (9)(10)(11)(12). To develop novel drugs, we have been recently focusing on cyclin-dependent protein kinases (CDKs), which are known to be used for virus replication (13)(14)(15)(16).…”

Indirubin 3′-Monoxime, from a Chinese Traditional Herbal Formula, Suppresses Viremia in Humanized Mice Infected with Multidrug-Resistant HIV

“…Despite the limitations of the animal model, 23 IM, and perhaps flavopiridol analogs 26 and recently developed mimetic CDK9 inhibitors, 27 may provide effective approaches for controlling HIV, particularly drug-resistant strains, in patients.…”