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Significance of endangered and threatened plant natural products in the control of human disease
Ibrahim, Mohamed Ali,Na, MinKyun,Oh, Joonseok,Schinazi, Raymond F.,McBrayer, Tami R.,Whitaker, Tony,Doerksen, Robert J.,Newman, David J.,Zachos, Louis G.,Hamann, Mark T. National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.42
<P>One in five of the world’s plant species is threatened with extinction according to the 2010 first global analysis of extinction risk. Tilman et al. predicted a massive ecological change to terrestrial plants within the next 50–100 y, accompanied by an increase in the number of global plant species facing extinction [Tilman D, et al. (2001) <I>Proc Natl Acad Sci USA</I> 98(10):5433–5440]. Most of the drug-producing plant families contain endangered species never previously studied for their utility to human health, which strongly validates the need to prioritize protection and assessment of these fragile and endangered groups [Zhu F, et al. (2011) <I>Proc Natl Acad Sci USA</I> 108(31):12943–12948]. With little prior attention given to endangered and rare plant species, this report provides strong justification for conservation of the rare plant <I>Diplostephium rhododendroides</I> Hieron., as well as other potential drug-producing endangered species in this and other groups.</P>
Nguyen, L.A.,Domaoal, R.A.,Kennedy, E.M.,Kim, D.H.,Schinazi, R.F.,Kim, B. Elsevier/North-Holland 2015 ANTIVIRAL RESEARCH Vol.115 No.-
Non-dividing macrophages maintain extremely low cellular deoxyribonucleotide triphosphate (dNTP) levels, but high ribonucleotide triphosphate (rNTP) concentrations. The disparate nucleotide pools kinetically forces Human Immunodeficiency Virus 1 (HIV-1) reverse transcriptase (RT) to incorporate non-canonical rNTPs during reverse transcription. HIV-1 RT pauses near ribonucleoside monophosphates (rNMPs) embedded in the template DNA, which has previously been shown to enhance mismatch extension. Here, pre-steady state kinetic analysis shows rNTP binding affinity (K<SUB>d</SUB>) of HIV-1 RT for non-canonical rNTPs was 1.4- to 43-fold lower, and the rNTP rate of incorporation (k<SUB>pol</SUB>) was 15- to 1551-fold slower than for dNTPs. This suggests that RT is more selective for incorporation of dNTPs rather than rNTPs. HIV-1 RT selectivity for dNTP versus rNTP is the lowest for ATP, implying that HIV-1 RT preferentially incorporates ATP when dATP concentration is limited. We observed that incorporation of a dNTP occurring one nucleotide before an embedded rNMP in the template had a 29-fold greater K<SUB>d</SUB> and a 20-fold slower k<SUB>pol</SUB> as compared to the same template containing dNMP. This reduced the overall dNTP incorporation efficiency of HIV-1 RT by 581-fold. Finally, the RT mutant Y115F displayed lower discrimination against rNTPs due to its increase in binding affinity for non-canonical rNTPs. Overall, these kinetic results demonstrate that HIV-1 RT utilizes both substrate binding and a conformational change during: (1) enzymatic discrimination of non-canonical rNTPs from dNTPs and (2) during dNTP primer extension with DNA templates containing embedded rNMP.
Sana Aslam,Matloob Ahmad,Muhammad Zia-ur-Rehman,Catherine Montero,Mervi Detorio,Masood Parvez,Raymond F. Schinazi 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.11
A novel series of N0-(1-(aryl)ethylidene)-2-(5,5-dioxido-3-phenylbenzo[e]pyrazolo[4,3-c][1,2]thiazin-4(1H)-yl)acetohydrazides was synthesized. The synthesiswas carried out by thermal method as well as ultrasonicbath to reduce reaction time and to enhance product yields. The synthesized compounds were characterized by spectroscopictechniques like NMR, infrared and EIMS. Thestructure of compound 5w was elucidated by X-ray crystallography. The titled compounds were evaluated for antihumanimmunodeficiency virus type 1 (anti-HIV-1) andcytotoxic activities. Biological studies indicated thatamongst these compounds, 5a, b, j, h and i showed theactivity with median effective concentration (EC50) valuesless than 20 lM. Compound 5i exhibited the most potentanti-HIV-1 activity (EC50 = 3.2 lM) while 5h showedanti-HIV-1 activity (EC50 = 3.8 lM) with no toxicity at allin primary human lymphocytes, CEM and VERO cells.
SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells
Bonifati, S.,Daly, M.B.,St. Gelais, C.,Kim, S.H.,Hollenbaugh, J.A.,Shepard, C.,Kennedy, E.M.,Kim, Dong.Hyun.,Schinazi, R.F.,Kim, B.,Wu, L. 3M Company 2016 Virology Vol.495 No.-
<P>SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G(1)/G(0) phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection. (C) 2016 Elsevier Inc. All rights reserved.</P>