Pollastri Michael P.

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Pollastri
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Michael P.
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  • Preprint
    Repurposing human PDE4 inhibitors for neglected tropical diseases : design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors
    ( 2014-07) Amata, Emanuele ; Bland, Nicholas D. ; Hoyt, Charles T. ; Settimo, Luca ; Campbell, Robert K. ; Pollastri, Michael P.
    A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.
  • Preprint
    Target repurposing for neglected diseases
    ( 2011-06-30) Pollastri, Michael P. ; Campbell, Robert K.
    Infectious diseases are an enormous burden to global health, and since drug discovery is costly, those infectious diseases that affect the developing world are often not pursued by commercial drug discovery efforts. Therefore, pragmatic means by which new therapeutics can be discovered are needed. One such approach is target repurposing, where pathogen targets are matched with homologous human targets that have been pursued for drug discovery for other indications. In many cases, the medicinal chemistry, structural biology, and biochemistry knowledge around these human targets can be directly repurposed to launch and accelerate new drug discovery efforts against the pathogen targets. This article describes the overarching strategy of target repurposing as a tool for initiating and prosecuting neglected disease drug discovery programs, highlighting this approach with three case studies.
  • Preprint
    Synthesis and assessment of catechol diether compounds as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)
    ( 2013-08-07) Woodring, Jennifer L. ; Bland, Nicholas D. ; Ochiana, Stefan O. ; Campbell, Robert K. ; Pollastri, Michael P.
    Human African trypanosomiasis (HAT) is a parasitic neglected tropical disease that affects 10,000 patients each year. Current treatments are sub-optimal, and the disease is fatal if not treated. Herein, we report our continuing efforts to repurpose the human phosphodiesterase 4 (hPDE4) inhibitor piclamilast to target trypanosomal phosphodiesterase TbrPDEB1. We prepared a range of substituted heterocyclic replacements for the 4-amino-3,5-dichloro-pyridine head group of piclamilast, and found that these compounds exhibited weak inhibitory activity of TbrPDEB1.
  • 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.
  • Preprint
    Evaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1)
    ( 2015-04-13) Amata, Emanuele ; Bland, Nicholas D. ; Campbell, Robert K. ; Pollastri, Michael P.
    Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis and assessment of a series of pyrrolidine and pyrazolone derivatives of human phosphodiesterase 4 (hPDE4) inhibitors for the assessment of their activity against the trypanosomal phosphodiesterase TbrPDEB1. The synthesized compounds showed weak potency against TbrPDEB1.
  • 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.