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

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.

Anti-infective Properties of the Golden Spice Curcumin

“…Despite this, a clinical study conducted in the 1990s could not find a decreased viral load or increased T-cell count in 40 HIV-patients treated with the molecule for 8 weeks (Gilden and Smart, 1996; James, 1996). Recently, new curcumin derivates or formulations with increased bioavailability and stability were developed against HIV (Kumari et al, 2015; Lin et al, 2017; Sharma et al, 2017; Zhao et al, 2017) and it has been shown that curcumin pretreatment of human genital epithelial cells blocks the infection-mediated induction of chemokines associated with the recruitment of HIV-target cells (Ferreira et al, 2015). Clinical assessment will show, whether these new curcumin variants and mechanisms of protection are effective in humans.…”

Antiviral Role of Phenolic Compounds against Dengue Virus: A Review

“…The antiviral activity of curcumin has been proven against many enveloped viruses, since this compound is able to modify the lipid bilayer and influences the function of the membrane protein [ 133 ]. The curcumin antiviral effect was confirmed for HBV inhibition of mRNA in HuS-E/2 (50 µM: more than 40%) [ 72 ]; for coxsackie virus (CVB3) in HeLa cells (MOI of 10; 30 µM) [ 134 ] and JEV in Neuro2a cells (MOI of 5; 5 and 10 μM) [ 135 ], acting as a host-target antiviral agent for both of these viruses by modulating ubiquitin–proteasome system; HSV-1 in pretreated VERO cells (MOI of 1; 10 μM) [ 136 ]; HIV by different mechanisms [ 137 ]; HCV entry in Huh-7.5 cells and primary human hepatocytes (IC 50 8.46 ± 1.27 mM in Huh-7.5 and 12.5 µM in PHH) [ 138 ]; and arboviruses like ZIKV and CHIKV in pretreated HeLa cells, inhibiting both infectious particle and viral-RNA (MOI of 0.1; IC 50 : 1.90 and 3.89 μM, respectively) [ 139 ].…”

Role of Divalent Cations in HIV-1 Replication and Pathogenicity

“…Protein phosphatase-1 (PP1) activity increases HIV-1 transcription, likely because of its effects on iron and HIF-1α. A low level of iron decreases PP1 catalytic activity and increases HIF-1α [218,219]. PP1 also increases HIV-1 transcription by releasing CDK9 from the inactive complex of 7SKRNP and HEXIM1 [220,221].…”