Despite medical advances fungal infections still exact a heavy burden on the HIV/AIDs population. AIDs-related fungal infections account for 50% of all AIDs-related deaths. In the developed world, AIDS-related fungal infections are most frequently associated with Candida albicans, but Aspergillus fumigatus and Cryptococcus neoformans are also common. Unfortunately, the number of treatments for invasive fungal infections has remained relatively stagnant. Also, the three most widely-used classes of antifungals collectively inhibit only a few molecular targets. As a consequence of their widespread use, an increasing numbers of invasive fungi are resistant to multiple antifungals. A promising new strategy to enhance the efficacy of antifungals and block the evolution of drug resistance is to inhibit the molecular chaperone heat shock protein 90 (Hsp90). .Hsp90, an essential molecular chaperone, regulates the stability of its client proteins, many of which are involved in stress responses. Fungi depend on these stress responses to cope with cell membrane and cell wall damage induced by antifungal drugs. Inhibiting Hsp90 would dismantle cellular stress response circuitry and thus, abrogate drug resistance and dramatically enhance the efficacy of antifungal medications. Previous research has demonstrated that an Hsp90 inhibitor abolished drug resistance in azole-resistant and echinocandin-resistant strains. Hsp90 inhibition also impairs the acquisition of resistance. When Hsp90 is depleted or inhibited in the yeast model organism Saccharomyces cerevisiae or in C. albicans, the evolution of resistance to azoles is impaired. While several Hsp90 inhibitors are in development for cancer treatment, these inhibitors work on both fungal and human Hsp90, thereby making them toxic as antifungals. Our compound, LP13371, could be an important advancement in treating fungal infections. To our knowledge, LP13371 is the first characterized small molecule that selectively inhibits fungal Hsp90. It works in combination with known antifungals against a broad range of pathogenic fungi. It is a novel, patentable, easily analoged, and small molecular weight compound that demonstrates a promising safety profile. Our overarching research plan is to advance LP13371 and/or its analogs as a pre-clinical candidate. We will synthesize LP13371, perform complete ADME experiments to determine its likely pharmacokinetic properties, measure its ability to retard fungal biofilm, and determine the efficacy and safety of LP13371in five in vivo mouse models. We will develop resistant strains of C. albicans to help define LP13371 s mechanism of action. Even though LP13371 has impressive activity and specificity in our assays, we will also synthesize analogs of LP13371 because they may have better in vivo properties. We will investigate these analogues in a manner similar to the above-mentioned process for LP13371. To accomplish these goals, we have assembled an excellent team, including Timo Ovaska, Professor of Chemistry at Connecticut College, Mahmoud A. Ghannoum, Director of The Center for Medical Mycology at Case Western Reserve University, and Leah Cowen, Assistant Professor at the University of Toronto.
Fungal infections continue to be a major cause of morbidity and mortality among HIV infected patients. There have been an increased number of varied and resistant fungal pathogens that are difficult to treat. Also, there are very few fungal specific targets that are appropriate for drug discovery. . A promising new strategy to enhance the efficacy of antifungals and block the evolution of drug resistance is to inhibit the molecular chaperone heat shock protein 90 (Hsp90). Hsp90, an essential molecular chaperone, regulates the stability of its client proteins, many of which are involved in stress responses. Fungi depend on these stress responses to cope with cell membrane and cell wall damage induced by antifungal drugs. Our compound could be an important advancement in treating fungal infections. To our knowledge, it is the first characterized small molecule that selectively inhibit fungal Hsp90. It works in combination with known antifungals against a broad range of pathogenic fungi. We intend to use this SBIRII to develop this compound and its analogs as a novel treatment for fungal infections.
