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O2-Glycosylated Diazeniumdiolates as Anti-Microbial Agents

Macrophages and the nitric oxide (NO) they produce on stimulation by appropriate cytokine combinations are key players in a mammalian host's defense against microbial pathogens and cancer cells, but they can fail in this role, allowing disease to progress. With the hypothesis that pharmacologic supplementation of the immune cells' NO output might restore their host-protective effects, the possibility that prodrugs exploiting the mannose receptor (MR) of macrophages might be actively imported and then selectively activated in the intracellular milieu for NO release and consequent therapeutic benefit was explored. As a test system,  Leishmania major (L. major), a protozoan parasite that is known to be susceptible to NO's toxic effects, but that is able to survive and proliferate in the highly lytic phagolysosomes of macrophages that have not yet been induced to express inducible NO synthase (iNOS) was chosen. Various monosaccharide-protected diazeniumdiolates showed that two N-acetylglucosamine (GlcNAc)-protected diazeniumdiolates (GlcNAc-DEA/NO and GlcNAc-PYRRO/NO at 250 μM) significantly decreased the parasite load in iNOS-deficient macrophages. There was no host cell toxicity observed at this concentration. The implication is receptor-mediated delivery of these drugs and their second-generation analogs might show similarly promising activity in situations involving other infectious diseases or cancer.

Anti-Microbial Agents diagram

O2-Glycosylated PROLI/NO and its metabolism to NO.