scholarly journals 1E7-03, a Small Molecule Targeting Host Protein Phosphatase-1, Inhibits HIV-1 Transcription

2014 ◽  
pp. n/a-n/a ◽  
Author(s):  
Tatyana Ammosova ◽  
Maxim Platonov ◽  
Andrei Ivanov ◽  
Yasemin Saygideğer Kont ◽  
Namita Kumari ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Phosphatase ◽  
Host Protein ◽  
Protein Phosphatase 1 ◽  
Hiv 1

scholarly journals Inhibition of HIV-1 infection in humanized mice and metabolic stability of protein phosphatase-1-targeting small molecule 1E7-03

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 76749-76769 ◽  
Author(s):  
Xionghao Lin ◽  
Namita Kumari ◽  
Catherine DeMarino ◽  
Yasemin Saygideğer Kont ◽  
Tatiana Ammosova ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Phosphatase ◽  
Metabolic Stability ◽  
Protein Phosphatase 1 ◽  
Humanized Mice ◽  
Hiv 1

scholarly journals Protein Phosphatase 1–Targeting Small-Molecule C31 Inhibits Ebola Virus Replication

2018 ◽  
Vol 218 (suppl_5) ◽  
pp. S627-S635 ◽  
Author(s):  
Tatiana Ammosova ◽  
Colette A Pietzsch ◽  
Yasemin Saygideğer ◽  
Andrey Ilatovsky ◽  
Xionghao Lin ◽  
...  
Keyword(s):  
Virus Replication ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Ebola Virus ◽  
Protein Phosphatase 1

Non-Competitive Protein Phosphatase-1 Inhibitors Prevent Sickling of SS RBCs.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4038-4038
Author(s):  
Jerod Hairston ◽  
Keon Combi ◽  
Altreisha Foster ◽  
Bak Kim ◽  
Victor R. Gordeuk ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Cultured Cells ◽  
Conflicts Of Interest ◽  
Protein Phosphatase 1 ◽  
Cell Protein ◽  
Trypan Blue Exclusion ◽  
Future Design ◽  
Small Molecular Inhibitors ◽  
Hiv 1

Abstract Abstract 4038 Poster Board III-974 Protein phosphatase-1 (PP1) has been implicated in the regulation of KCC (K:Cl) transporters, which transport K+ and Cl- ions from red blood cells (RBCs) and in the setting of sickle cell disease may contribute to RBC dehydration and sickling. We have studied host cell protein phosphatase-1 (PP1) in the context of HIV-1 replication and designed novel small molecule non-competitive inhibitors of PP1 that are efficient in the inhibition of HIV-1 but not toxic for cultured cells. We analyzed the effect of our novel non-competitive PP1 inhibitors and the conventional competitive PP1 inhibitor, ocadaic acid, on the sickling of hemoglobin SS RBCs in vitro. We cultured hemoglobin SS RBCs overnight at 1% O2 in the presence of the PP1 inhibitors and then photographed the RBCs and counted the percentage of sickled RBCs. We found that the non-competitive PP1 inhibitor, 1E7-04 prevented RBC sickling by 40% at 10 mM concentration. The 1E7-04 was not toxic at 10 mM concentration for cultured CEM T cells as determined by trypan blue exclusion assay using an automatic cell counter. Our study suggests that small molecular inhibitors of PP1 might be candidates for the future design of anti-sickling drugs. Acknowledgments. This work was supported by NHLBI grant U54HL090508-02; NHLBI grant R25 HL003679-08 from the National Institute of Helath and The Office of Research on Minority Health and by U.S. Civilian Research & Development Foundation grant. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Compensatory Substitutions in the HIV-1 Capsid Reduce the Fitness Cost Associated with Resistance to a Capsid-Targeting Small-Molecule Inhibitor

2014 ◽  
Vol 89 (1) ◽  
pp. 208-219 ◽  
Author(s):  
Jiong Shi ◽  
Jing Zhou ◽  
Upul D. Halambage ◽  
Vaibhav B. Shah ◽  
Mallori J. Burse ◽  
...  
Keyword(s):  
Amino Acid ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Binding Pocket ◽  
Host Protein ◽  
Viral Capsid ◽  
Inhibitory Protein ◽  
Hiv 1 ◽  
Ca Protein

ABSTRACTThe HIV-1 capsid plays multiple roles in infection and is an emerging therapeutic target. The small-molecule HIV-1 inhibitor PF-3450074 (PF74) blocks HIV-1 at an early postentry stage by binding the viral capsid and interfering with its function. Selection for resistance resulted in accumulation of five amino acid changes in the viral CA protein, which collectively reduced binding of the compound to HIV-1 particles. In the present study, we dissected the individual and combinatorial contributions of each of the five substitutions Q67H, K70R, H87P, T107N, and L111I to PF74 resistance, PF74 binding, and HIV-1 infectivity. Q67H, K70R, and T107N each conferred low-level resistance to PF74 and collectively conferred strong resistance. The substitutions K70R and L111I impaired HIV-1 infectivity, which was partially restored by the other substitutions at positions 67 and 107. PF74 binding to HIV-1 particles was reduced by the Q67H, K70R, and T107N substitutions, consistent with the location of these positions in the inhibitor-binding pocket. Replication of the 5Mut virus was markedly impaired in cultured macrophages, reminiscent of the previously reported N74D CA mutant. 5Mut substitutions also reduced the binding of the host protein CPSF6 to assembled CA complexesin vitroand permitted infection of cells expressing the inhibitory protein CPSF6-358. Our results demonstrate that strong resistance to PF74 requires accumulation of multiple substitutions in CA to inhibit PF74 binding and compensate for fitness impairments associated with some of the sequence changes.IMPORTANCEThe HIV-1 capsid is an emerging drug target, and several small-molecule compounds have been reported to inhibit HIV-1 infection by targeting the capsid. Here we show that resistance to the capsid-targeting inhibitor PF74 requires multiple amino acid substitutions in the binding pocket of the CA protein. Three changes in CA were necessary to inhibit binding of PF74 while maintaining viral infectivity. Replication of the PF74-resistant HIV-1 mutant was impaired in macrophages, likely owing to altered interactions with host cell factors. Our results suggest that HIV-1 resistance to capsid-targeting inhibitors will be limited by functional constraints on the viral capsid protein. Therefore, this work enhances the attractiveness of the HIV-1 capsid as a therapeutic target.

Hypoxia Inhibits HIV-1 Transcription.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1305-1305
Author(s):  
Sergei Nekhai ◽  
Charles Sharroya ◽  
Tatyana Ammosova ◽  
Xiaomei Nui ◽  
Marina Jerebtsova ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Oxygen Tension ◽  
Protein Phosphatase ◽  
Tissue Oxygenation ◽  
Protein Phosphatase 1 ◽  
Tat Protein ◽  
Cyclin T1 ◽  
Hiv Transcription ◽  
Hiv 1

Abstract The hypoxic response is an important component of the body’s reaction to impaired tissue oxygenation associated with the anemia and vasoocclusive episodes of sickle cell disease (SCD). It has been reported that HIV infection progresses relatively slowly in patients with SCD (Am J Hematol1998;59:199–207). HIV-1 Tat protein promotes transcription of HIV-1 genes by inducing CDK9/cyclin T1 to phosphorylate the C-terminal domain of RNA polymerase-II. Our previous studies indicate that protein phosphatase-1 (PP1) promotes Tat-induced HIV-1 transcription (J Biol Chem2003;278:32189–941), apparently by interacting with HIV-1 Tat, for disruption of this interaction prevents induction of transcription (J Biol Chem2005;280:36364–71). Recently PP1 activity was shown to be decreased in hypoxia in part through increased association of PP1 with NIPP1 (J Cell Physiol 2006 Jul 6; Epub ahead of print). We hypothesized that decreased PP1 activity during hypoxia would reduce HIV-1 transcription and viral replication, and we have obtained experimental results consistent with this hypothesis.Increased expression of nuclear inhibitor of PP1 (NIPP1) was associated with inhibition of HIV-1 transcription and viral replication.Low oxygen tension (3%–6% O2) was associated with transient inhibition of HIV-1 transcription in transfected 293T and HeLa cells.Low oxygen tension was associated with inhibition of HIV-1 transcription in CEM T cells infected with pseudotyped HIV-1 virus. We are now planning to examine the possible role of altered PP1 activity in the observed inhibition of HIV-1 transcription during hypoxia. Thus, a clinical insight from patients with SCD has pointed the way to investigating the influence of hypoxia on HIV transcription. An improved understanding of how oxygen status influences viral activation versus inactivation might open new possibilities for treatment of hidden HIV-1 reservoirs that harbor non-replicating HIV-1 virus.

scholarly journals Nuclear Protein Phosphatase-1 Regulates HIV-1 Transcription

2003 ◽  
Vol 278 (34) ◽  
pp. 32189-32194 ◽  
Author(s):  
Tatyana Ammosova ◽  
Marina Jerebtsova ◽  
Monique Beullens ◽  
Yaroslav Voloshin ◽  
Patricio E. Ray ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Nuclear Protein ◽  
Protein Phosphatase 1 ◽  
Hiv 1

scholarly journals Small Molecules Targeted to a Non-Catalytic “RVxF” Binding Site of Protein Phosphatase-1 Inhibit HIV-1

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e39481 ◽  
Author(s):  
Tatiana Ammosova ◽  
Maxim Platonov ◽  
Venkat R. K. Yedavalli ◽  
Yuri Obukhov ◽  
Victor R. Gordeuk ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Site ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Hiv 1

scholarly journals Expression of a Protein Phosphatase 1 Inhibitor, cdNIPP1, Increases CDK9 Threonine 186 Phosphorylation and Inhibits HIV-1 Transcription

2010 ◽  
Vol 286 (5) ◽  
pp. 3798-3804 ◽  
Author(s):  
Tatiana Ammosova ◽  
Venkat R. K. Yedavalli ◽  
Xiaomei Niu ◽  
Marina Jerebtsova ◽  
Aleyde Van Eynde ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Hiv 1
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