Research Papers:
Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03
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Abstract
Xionghao Lin1, Namita Kumari1, Catherine DeMarino6, Yasemin Saygideğer Kont5, Tatiana Ammosova1,2,8, Amol Kulkarni4, Marina Jerebtsova3, Guelaguetza Vazquez-Meves1, Andrey Ivanov1, Dmytro Kovalskyy7, Aykut Üren5, Fatah Kashanchi6 and Sergei Nekhai1,2,3
1Center for Sickle Cell Disease, College of Medicine, Howard University, Washington, DC, USA
2Department of Medicine, College of Medicine, Howard University, Washington, DC, USA
3Department of Microbiology, College of Medicine, Howard University, Washington, DC, USA
4Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC, USA
5Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
6Laboratory of Molecular Virology, George Mason University, Manassas, VA, USA
7Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA
8Yakut Science Center for Complex Medical Problems, Yakutsk, Russia
Correspondence to:
Sergei Nekhai, email: [email protected]
Keywords: HIV-1, protein phosphatase-1, small molecule HIV-1 inhibitor, HIV-1 infected humanized mice, metabolic stability
Received: March 22, 2017 Accepted: July 14, 2017 Published: August 07, 2017
ABSTRACT
We recently identified the protein phosphatase-1 - targeting compound, 1E7-03 which inhibited HIV-1 in vitro. Here, we investigated the effect of 1E7-03 on HIV-1 infection in vivo by analyzing its metabolic stability and antiviral activity of 1E7-03 and its metabolites in HIV-1 infected NSG-humanized mice. 1E7-03 was degraded in serum and formed two major degradation products, DP1 and DP3, which bound protein phosphatase-1 in vitro. However, their anti-viral activities were significantly reduced due to inefficient cell permeability. In cultured cells, 1E7-03 reduced expression of several protein phosphatase-1 regulatory subunits including Sds22 as determined by a label free quantitative proteomics analysis. In HIV-1-infected humanized mice, 1E7-03 significantly reduced plasma HIV-1 RNA levels, similar to the previously described HIV-1 transcription inhibitor F07#13. We synthesized a DP1 analog, DP1-07 with a truncated side chain, which showed improved cell permeability and longer pharmacokinetic retention in mice. But DP1-07 was less efficient than 1E7-03 as a HIV-1 inhibitor both in vitro and in vivo, indicating that the full side chain of 1E7-03 was essential for its anti-HIV activity. Analysis of 1E7-03 stability in plasma and liver microsomes showed that the compound was stable in human, primate and ferret plasma but not in rodent plasma. However, 1E7-03 was not stable in human liver microsomes. Our findings suggest that 1E7-03 is a good candidate for future development of HIV-1 transcription inhibitors. Further structural modification and advanced formulations are needed to improve its metabolic stability and enhance its antiviral activity in non-human primate animals and humans.
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PII: 19999