In VitroActivity of Geldanamycin Derivatives againstSchistosoma japonicumandBrugia malayi

Abstract

Geldanamycin (GA) is a benzoquinone-containing ansamycin that inhibits heat shock protein 90. GA derivatives are being evaluated as anti-neoplastic agents, but their utility against parasites whose heat shock proteins (Hsps) have homology with human Hsp90 is unknown. The activities of four synthetic GA derivatives were tested in vitro using adult Brugia malayi and Schistosoma japonicum. Two of the derivatives, 17-N-allyl-17-demethoxygeldanamycin (17-AAG) and 17-N-(2-dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), are currently in human clinical trials as anticancer drugs. Using concentrations considered safe peak plasma concentrations for these two derivatives, all four derivatives were active against both parasites. The less toxic derivative 17-AAG was as effective as GA in killing S. japonicum, and both DMAG and 5′-bromogeldanoxazinone were more active than 17-AAG against B. malayi. This work supports continued evaluation of ansamycin derivatives as broad spectrum antiparasitic agents.

Chemotherapeutic Potential of 17-AAG against Cutaneous Leishmaniasis Caused by Leishmania (Viannia) braziliensis

“…HSP90 is a molecular chaperone fundamental for the life cycle of a variety or protozoa [31] and, as such, inhibitors of HSP90 have been suggested as novel chemotherapeutic agents against malaria [32] , filariasis [33] , [34] and schistosomiasis [34] . Recently, we showed that 17-AAG, a HSP90 inhibitor, reduced L. (L.) amazonensis infection in vitro [24] .…”

Enhanced Intradermal Delivery of Nanosuspensions of Antifilariasis Drugs Using Dissolving Microneedles: A Proof of Concept Study

“…The great distribution of drugs after intradermal administration using MNs in combination with NS approach could potentially lead to the high possibility of lymphatic capillaries in dermis layer to take up the particles. With respect to the concentration of these drugs required to kill filarial nematodes, it was reported that 40 µg/mL of DOX [12], 26.53 µg/mL of ABZ [57], and 170 µg/mL of IVM [58] were able to kill Brugia malayi in vitro after 7 days, 16 days, and 4 days, respectively. These concentrations were around 2–10 times lower than the C max obtained in the dermatokinetic study.…”

Anti-malarial activity of geldanamycin derivatives in mice infected with Plasmodium yoelii

“…Macro-filaricidal activity of GA against cat and dog filaria has also been reported [39]. Recent observations about the ability of GA to kill adult male and female worms of Brugia malayi (that causes lymphatic filariasis] and Schistosoma japonicum (that causes schistosomiasis) suggests possibilities of wider therapeutic potential of this drug [40]. GA resistant homolog of HSP90 has been reported in nematode Caenorhabditis elegans [41,42] raising the possibility for the quick emergence of resistance against the drug.…”