Pilot Award Recipient: Xionghao Lin, PhD

Small Molecule Inhibitors of Tat Dependent HIV-1 Transcription

June 04, 2019

Human immunodeficiency virus-1 (HIV-1) remains a severe burden worldwide. According to the Centers for Disease Control and Prevention (CDC), District of Columbia (D.C.) has the worst record for number of HIV infections in US. While HIV/AIDS can be managed with current antiretroviral drugs, these agents are incapable of clearing the virus and do not target HIV transcription that is reactivated if the treatment is interrupted. HIV-1 Tat, as one of the early viral proteins, plays a pivotal role in HIV-1 transcriptional activation. Dideydro-Cortistatin A (dCA), a selective inhibitor for HIV-1 Tat, has been shown to delay viral rebound both in cell culture and in mouse model. However, dCA has yet been tested in clinical trial and there are no Tat inhibitors clinically available thus far. Therefore, developing new classes of anti-HIV-1 drugs by targeting Tat dependent transcription may lead to a HIV-1 functional cure by permanently driving HIV-1 into deep latency. Previously, their lab has identified compound 1E7-03 as the optimum protein phosphatase 1 (PP1)- targeting HIV-1 transcription inhibitor that significantly inhibits HIV-1 both in cell culture and in HIV-1 infected humanized mice. They recently performed a shape-based screening in ChemDiv chemical database using 1E7-03 as a template. A novel compound CD52 showed more efficient (4-fold) on HIV-1 inhibition comparing to 1E7-03. CD52 preferentially inhibited Tat-dependent HIV-1 transcription rather than basal HIV-1 transcription (over 100-fold difference on IC50s), while 1E7-03 showed similar inhibition on Tat-dependent and basal HIV-1 transcription. Importantly, CD52 is a novel scaffold different from known Tat inhibitors. The anti-viral mechanism of CD52 scaffold has not been explored.

They propose to perform the SAR analysis of CD52 scaffold to establish an innovative shape based computational model for further discovery of novel HIV-1 inhibitors by targeting Tat dependent transcription to identify the cellular targets of CD52 scaffold using (stable isotope labeling by amino acids in cell culture) SILAC based quantitative proteomics method. We expect to receive a new class of HIV-1 inhibitors that could be used alone or in combination of current anti-retroviral drugs. The study will also provide new insights on antiviral mechanisms that could be further used to develop new therapies for HIV-1 cure.