Protease Inhibitors Could Be Effective For Fungal Disease


chromoblastomycosisChromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissue most commonly caused by infection with Fonsecaea pedrosoi. The disease occurs most often in rural areas in tropical and subtropical countries and is caused when fungus is introduced by minor injury such as that caused by a splinter or thorn. Chromoblastomycosis is very difficult to cure; antifungal chemotherapy, surgical excision and/or cryosurgery have traditionally been used but with varying degrees of success.

Recently, HIV protease inhibitors have been shown to have a direct effect on AIDS-related opportunistic pathogens such as Candida albicans by inhibiting production of C. albicans secreted aspartyl proteases. The proteases assist the fungus to colonize tissues and to evade the host’s antimicrobial defense mechanisms. F. Pedrosoi also secretes aspartyl proteases and a study published in PloS ONE describes the effect of selected HIV protease inhibitors on secreted protease activity and survival of F. Pedrosoi. At high concentration (100µM), saquinavir and nelfinavir robustly inhibited growth of F. Pedrosoi in vitro. The high concentration needed possibly reflects a much lower affinity for the fungal protease than for HIV protease, or may suggest alternative mechanisms of control. The authors also studied the in vitro effect of combining sub-inhibitory concentrations of the aspartyl protease inhibitors with sub-inhibitory concentrations of antifungal drugs and found good synergistic actions.

The results suggest that combination therapy with protease inhibitors and antimycotic drugs may be effective for treatment of chromoblastomycosis, especially if more potent inhibitors of the F. Pedrosoi aspartyl protease were developed.

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