XMP Antifungal Peptides Demonstrate Enhanced Selectivity and Oral Availability.

R. LITTLE, E. LIM, P. WONG, A. MALLADI, J. WILSON, J. LIN, K. GIKONYO, M. BAKALINSKY, P. MOTCHNIK, and S. ABRAHAMSON

Abstract: 

A rational library screening program of antifungal compounds based on functional domain III of bactericidal/permeability-increasing protein (BPI) continues to produce new, broad spectrum fungicidal compounds with improved fungal selectivity. Molecules designed for systemic administration were optimized for protective effects in a murine candidiasis mortality model. Lead compounds have emerged from a series of assays designed to produce safe and potent fungicidal agents. In vitro fungicidal activity in broth and radial diffusion assays selected for potency on Candida and Aspergillus species. Secondary in vitro screening assays selected compounds with serum stability and excellent (50-fold) separation between antifungal activity and mammalian cell toxicity using a FACS-based carbocyanine metabolic dye (DiOC_{6} (3). Final screening in a murine model of candidiasis using an alternate day dosing regimen selected for compounds with large therapeutic windows and potent efficacy using low doses. For example, XMP.445 has an MIC = 16 micro g/ml in defined Yeast Nitrogen Broth/Asparagine medium and protects in the candidiasis model using 0.5mg/kg intravenous doses. Antifungal compounds designed for oral administration (* 1000 daltons) have been synthesized and screened for activity and oral absorption using CACO-2 and MDCK cells. These cell lines form confluent monolayers and serve as models of intestinal absorption. Compounds with significant transport across the monolayers were initially tested for intravenous efficacy using the murine candidiasis model. Those compounds with significant systemic protection were then analyzed for oral availability and efficacy in mice. Screening of our initial compounds has produced active constructs that can achieve blood levels above or equivalent to MIC values after a 10 or 20 mg/kg oral dose. In summary, our screening program has produced systemically active and orally available, broad spectrum antifungal compounds from BPI. This class of compounds demonstrate potent antifungal activity and low mammalian cell toxicity. Thus, our rational design screening program has produced novel compounds which have rapidly evolved from initial leads to prototypes for potential use in human systemic fungal infections.
1998

abstract No: 

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Full conference title: 

38th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 38th