Activation of HIV-1 with Nanoparticle-Packaged Small-Molecule Protein Phosphatase-1-Targeting Compound

Kahli A Smith; Xionghao Lin; Oleg Bolshakov; James Griffin; Xiaomei Niu; Dmytro Kovalskyy; Andrey Ivanov; Marina Jerebtsova; Robert E Taylor; Emmanuel Akala; Sergei Nekhai

doi:10.3797/scipharm.1502-01

Activation of HIV-1 with Nanoparticle-Packaged Small-Molecule Protein Phosphatase-1-Targeting Compound

Sci Pharm. 2015 Jun 22;83(3):535-48. doi: 10.3797/scipharm.1502-01. Print 2015 Jul-Sep.

Authors

Affiliations

¹ Center for Sickle Cell Disease, Howard University, Washington DC 20059, USA; Department of Pharmacology, Howard University, Washington DC 20059, USA.
² Center for Sickle Cell Disease, Howard University, Washington DC 20059, USA.
³ Department of Pharmaceutical Sciences, Howard University, Washington DC 20059, USA.
⁴ College of Engineering, Howard University, Washington DC 20059, USA.
⁵ Department of Biochemistry, School of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio TX 78229, USA; Enamine LLC, Princeton Corporate Plaza, 7 Deer Park Drive, Ste. M-3 Monmouth Jct., NJ 08852, USA.
⁶ Department of Microbiology, College of Medicine, Howard University, Washington DC 20059, USA.
⁷ Department of Pharmacology, Howard University, Washington DC 20059, USA.
⁸ Center for Sickle Cell Disease, Howard University, Washington DC 20059, USA; Department of Pharmacology, Howard University, Washington DC 20059, USA; Department of Microbiology, College of Medicine, Howard University, Washington DC 20059, USA; Department of Medicine, Howard University, Washington DC 20059, USA.

Abstract

Complete eradication of HIV-1 infection is impeded by the existence of latent HIV-1 reservoirs in which the integrated HIV-1 provirus is transcriptionally inactive. Activation of HIV-1 transcription requires the viral Tat protein and host cell factors, including protein phosphatase-1 (PP1). We previously developed a library of small compounds that targeted PP1 and identified a compound, SMAPP1, which induced HIV-1 transcription. However, this compound has a limited bioavailability in vivo and may not be able to reach HIV-1-infected cells and induce HIV-1 transcription in patients. We packaged SMAPP1 in polymeric polyethylene glycol polymethyl methacrylate nanoparticles and analyzed its release and the effect on HIV-1 transcription in a cell culture. SMAPP1 was efficiently packaged in the nanoparticles and released during a 120-hr period. Treatment of the HIV-1-infected cells with the SMAPP1-loaded nanoparticles induced HIV-1 transcription. Thus, nanoparticles loaded with HIV-1-targeting compounds might be useful for future anti-HIV-1 therapeutics.

Keywords: HIV-1; Latency; Nanoparticles; PP1; SMAPP1; Small molecules; Transcription.

Abstract

Grants and funding