Immunoassays for pentamidine and related compounds: Development of a facile inhibitory ELISA suitable for clinical use

Reisner, H; Gray, Danny R.; Jones, Susan; Rose, Beate G.; Tidwell, Richard R.

doi:10.1002/(sici)1098-2825(2000)14:2<73::aid-jcla7>3.0.co;2-g

Cited by 3 publications

(2 citation statements)

References 34 publications

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“…The following classes of drugs have shown anti-Pneumocystis activity in rats and/or mice: antifolate compounds, including inhibitors of dihydropteroate synthase (sulfonamides, sulfones, and sulfonylureas) alone or in combination with inhibitors of dihydrofolate reductase (DHFR) [5,6,14,92,[111][112][113][114][115][116][117][118]; sulfonamides combined with macrolides [119][120][121]; diamidines and related cationionic compounds [44,72,[122][123][124][125][126][127][128][129][130][131][132][133][134][135][136][137][138]; 8aminoquinolones alone or combined with clindamycin [139][140][141][142]; purine nucleoside analogues [117,143]; polyamine inhibitors [144][145][146][147][148]...…”

Section: Active Drugsmentioning

confidence: 99%

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Cushion

Walzer²

2009

CMC

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Pneumocystis remains an important cause of fatal pneumonia (PCP) in HIV patients and other immunocompromised hosts. Preclinical drug discovery for agents active against PCP has been hindered in large part by the lack of a continuous in vitro growth system. Since approval in 1978, the combination of the folic acid synthesis inhibitor combination trimethoprim-sulfamethoxazole has been the primary agent for prophylaxis and therapy. Short term in vitro assays using cell monolayer-based and cell free systems in combination with in vivo studies in rodent models of infection have been the mainstay of candidate screening methods. These systems and their applications are reviewed here. Most strategies have focused on testing compounds already in clinical use, such as dapsone or atovaquone, for activity against Pneumocystis alone or in combination, and as parent compounds for chemical derivation, such as pentamidine and its analogues. Other successes from the bench include primaquine-clindamycin for moderate pneumonia and the family of Beta-glucan synthase inhibitors, which hold promise for clinical use against PCP. Despite the significant obstacles for drug discovery, progress in identifying novel agents has been made with current systems and the promise of future new targets is expected with the annotation of the Pneumocystis genome.

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Section: Active Drugsmentioning

confidence: 99%

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Cushion

Walzer²

2009

CMC

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“…jiroveci pneumonia (PCP) in the treatment of AIDS patients [4]. However, despite its clinical usefulness it exhibits a number of serious adverse effects [5].…”

Section: Introductionmentioning

confidence: 99%

Novel pentamidine derivatives: Synthesis, anti-tumor properties and polynucleotide-binding activities

Jarak¹,

Marjanović²,

Piantanida³

et al. 2011

European Journal of Medicinal Chemistry

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Novel amidino substituted conformationally restricted derivatives of pentamidine were synthesized and their antiproliferative activity against several human cancer cell lines determinated. It was found that introduction of furandicarboxamide core moiety (9, 10) increases antiproliferative activity as well as selectivity against certain tumor cell lines in comparison with amidino-substituted furan-mono-carboxamide (5, 6). Unlike the furan series where iso-propyl substituted amidine (10) exhibits more potent overall antiproliferative activity and selectivity toward certain cell lines, the same was found for unsubstituted amidines in pyridine series. Amongst all tested compounds the compound 10 is the only one that possesses antiproliferative activity against SW 620 cell line (4 µM). Spectroscopic studies of the interactions of prepared diamidines with double stranded DNA and RNA polynucleotides show that all compounds preferentially bind into the minor groove of DNA, while most of them intercalate into RNA. The structure-dependant biological activity and the lack of DNA/RNA selective binding suggest that the mechanism of action of the herepresented compounds is controlled not only by the interactions with cellular nucleic acids, but also with other more specific protein targets.

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Application of monoclonal antibodies to measure metabolism of an anti‐trypanosomal compound in vitro and in vivo

Goldsmith

Gray

Yan

et al. 2010

Clinical Laboratory Analysis

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Human African trypanosomiasis (HAT), also called African sleeping sickness, is a neglected tropical parasitic disease indigenous to sub-Saharan Africa. Diamidine compounds, including pentamidine and CPD-0801, are potent anti-trypanosomal molecules. The latter is a potential drug in the development at the UNC based Consortium for Parasitic Drug Development. An orally bioavailable prodrug of CPD-0801, DB868, is metabolized primarily in the liver to the active form. A monoclonal antibody developed against a pentamidine derivative has shown significant reactivity with CPD-0801 (EC(50) 65.1 nM), but not with the prodrug (EC(50)>18,000 nM). An inhibitory enzyme-linked immunosorbent assay (IELISA) has been used to quantitatively monitor prodrug metabolism by detecting the production of the active compound over time in a sandwich culture rat hepatocyte system and in rats. These results were compared with the results of the standard LC/MS/MS assay. Spearman coefficients of 0.96 and 0.933 (in vitro and in vivo, respectively) indicate a high correlation between these two measurement methods. This novel IELISA provides a facile, inexpensive, and accurate method for drug detection that may aide in elucidating the mechanisms of action and toxicity of existing and future diamidine compounds.

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Immunoassays for pentamidine and related compounds: Development of a facile inhibitory ELISA suitable for clinical use

Cited by 3 publications

References 34 publications

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Preclinical Drug Discovery for New Anti-Pneumocystis Compounds

Novel pentamidine derivatives: Synthesis, anti-tumor properties and polynucleotide-binding activities

Application of monoclonal antibodies to measure metabolism of an anti‐trypanosomal compound in vitro and in vivo

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