Pollastri Michael P.

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Pollastri
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Michael P.
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Author: Wang, Cuihua ×

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  • Preprint
    Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs
    ( 2012-01) Wang, Cuihua ; Ashton, Trent D. ; Gustafson, Alden ; Bland, Nicholas D. ; Ochiana, Stefan O. ; Campbell, Robert K. ; Pollastri, Michael P.
    Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. In this report we describe target repurposing efforts focused on trypanosomal phosphodiesterases. We outline the synthesis and biological evaluation of analogs of sildenafil (1), a human PDE5 inhibitor, for activities against trypanosomal PDEB1 (TbrPDEB1). We find that, while low potency analogs can be prepared, this chemical class is a sub-optimal starting point for further development of TbrPDE inhibitors.
  • Article
    Identification of cinnabarinic acid as novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production
    (Public Library of Science, 2014-02-03) Lowe, Margaret M. ; Mold, Jeff E. ; Kanwar, Bittoo ; Huang, Yong ; Louie, Alexander ; Pollastri, Michael P. ; Wang, Cuihua ; Patel, Gautam ; Franks, Diana G. ; Schlezinger, Jennifer ; Sherr, David H. ; Silverstone, Allen E. ; Hahn, Mark E. ; McCune, Joseph M.
    The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.
  • Preprint
    Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 2. Tadalafil analogs
    ( 2012-02-02) Ochiana, Stefan O. ; Gustafson, Alden ; Bland, Nicholas D. ; Wang, Cuihua ; Russo, Michael J. ; Campbell, Robert K. ; Pollastri, Michael P.
    In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.