Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

Title:Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals

Volume: 23 Issue: 28

Author(s): Xionghao Lin, Tatyana Ammosova, Namita Kumari and Sergei Nekhai*

Affiliation:

• Center for Sickle Cell Disease, 1840 7th Street, N.W. HURB1, Suite 202, Washington DC 20001,United States

Keywords: HIV-1, Tat, CDK9, CDK2, protein phosphatase-1, iron chelators, curcumin.

Abstract: Background: Despite efficient suppression of HIV-1 replication, current antiviral drugs are not able to eradicate HIV-1 infection. Permanent HIV-1 suppression or complete eradication requires novel biological approaches and therapeutic strategies. Our previous studies showed that HIV-1 transcription is regulated by host cell protein phosphatase-1. We also showed that HIV-1 transcription is sensitive to the reduction of intracellular iron that affects cell cycle-dependent kinase 2. We developed protein phosphatase 1-targeting small molecules that inhibited HIV-1 transcription. We also found an additional class of protein phosphatase-1-targeting molecules that activated HIV-1 transcription and reported HIV-1 inhibitory iron chelators and novel curcumin analogs that inhibit HIV-1. Here, we review HIV-1 transcription and replication with focus on its regulation by protein phosphatase 1 and cell cycle dependent kinase 2 and describe novel small molecules that can serve as future leads for anti-HIV drug development.

Results: Our review describes in a non-exhaustive manner studies in which HIV-1 transcription and replication are targeted with small molecules. Previously, published studies show that HIV-1 can be inhibited with protein phosphatase-1-targeting and iron chelating compounds and curcumin analogs. These results are significant in light of the current efforts to eradicate HIV-1 through permanent inhibition. Also, HIV-1 activating compounds can be useful for “kick and kill” therapy in which the virus is reactivated prior to its inhibition by the combination antiretroviral therapy.

Conclusion: The studies described in our review point to protein phosphatase-1 as a new drug target, intracellular iron as subject for iron chelation and novel curcumin analogs that can be developed for novel HIV-1 transcription- targeting therapeutics.

Cite this article as:

Lin Xionghao , Ammosova Tatyana , Kumari Namita and Nekhai Sergei*, Protein Phosphatase-1 –targeted Small Molecules, Iron Chelators and Curcumin Analogs as HIV-1 Antivirals, Current Pharmaceutical Design 2017; 23 (28) . https://dx.doi.org/10.2174/1381612823666170704123620