Heat Shock Protein Inhibitors for the Treatment of Fungal Infections

Baldeep      Wirk

doi:10.2174/157489111794407840

Abstract

Invasive fungal infections are a leading cause of mortality, especially in immunocompromised patients. Therapy is made difficult by the limited number of antifungal agents currently available which mostly target ergosterol in fungal cell membranes. The paucity of targets allows the development of cross resistance to all drugs with a common target. This highlights the need to develop new therapeutic strategies for fungal disease including agents with novel mechanisms of action. Heat shock protein 90 stabilizes calcineurin which regulates response to stress, allowing for calcineurin dependent stress responses required to survive exposure to antifungal drugs. Heat shock protein 90 inhibition abrogates calcineurin dependent stress responses, changing fungistatic drugs to fungicidal. Targeting a highly conserved protein that has a vital role in many cellular signaling pathways, reduces the potential for emergence of resistance to heat shock proteins inhibitors. This article will review recent patents in novel heat shock protein inhibitor therapy, such as efungumab, which diminish the emergence of antifungal drug resistance and enable greater efficacy of existing antifungals.

Keywords: Heat shock protein 90, fungal infections, immunocompromised, efungumab, 17-AAG, geldanamycin, Heat Shock Protein, antifungal agents, ergosterol, calcineurin, candidiasis, neutropenia, peritoneal dialysis, cerebrospinal fluid, C. albicans, C. krusei, C. lusitaniae, C. dubliniensis, C. tropicalis, C. pseudotropicalis, C. parapsilosis, C. inconspicua, fluconazole, invasive aspergillosis, Aspergillus fumigatus, C. lusitanae, Cryptococcus neoformans, amphotericin, itraconazole, voriconazole, posaconazole, echinocandins, caspofungin, anidulafungin, micafungin, D-glucan, cell mediated immunity, Hsp90, Gyrase, Hsp90, Histidine kinase, mut L kinase, trastuzumab, imatinib, tamoxifen, bicalutamide, Streptomyces hygroscopicus, cDNA