Novel inhibitors of DXP synthase as anti-infective drugs

Invention novelty:  novel class of chemical inhibitors targeting DXP synthase with increased selectivity to pathogens
 
Value Proposition: Development of anti-infectives has direct impact on infectious diseases such as malaria and tuberculosis. The long term goal is to develop novel, potent and broad-based anti-microbial agents that also exhibit limited toxicity to the human host. This technology is focused on a novel class of chemical inhibitors, which exhibit chemistry that is unique to DXP synthase, a potentially promising yet insufficiently explored drug target. The group of inhibitors synthesized in this technology targets DXP synthase, the enzyme involved in the first and rate-limiting step of isoprenoid pathway. Advantages of this technology include:

• novel class of chemical inhibitors targeting the isoprenoid synthesis pathway of pathogens
• increased selectively to inhibit DXP synthase in pathogens and reduced off-target effects to mammalian enzymes

 
Technical Details: Johns Hopkins researchers developed a group of novel inhibitors for DXP synthase, the enzyme involved in the first and rate-limiting step of isoprenoid biosynthesis in pathogens. Researchers have synthesized a group of aromatic acylphosphonates which selectively inhibits DXP synthase.  DXP synthase share a similar cofactor binding site with other ThDP-dependent enzymes: TK (transketolase) and PDH (pyruvate dehydrogenase E1 subunit). Previously reported DXP synthase inhibitors exhibited toxicity against mammalian cells due to off-target activity against mammalian ThDP-dependent enzymes. The developed novel inhibitors, aromatic acylphosphonates can be utilized as unnatural bisubstrate analogs which are selective inhibitors against DXP synthase. The results suggest that incorporation of aryl acceptor substrate mimics into unnatural bisubstrate analogs will impart selectivity to DXP synthase inhibitors. This technology identifies a unique inhibition mechanism in ThDP-dependent enzymology, and suggests a new direction for synthesizing inhibitors against early stage isoprenoid biosynthesis.
 
Looking for Partners: To develop & commercialize the technology as anti-infective therapeutics.
 
Stage of Development: Pre-Clinical
 
Data Availability: Under CDA / NDA
 
Patent Status: Pending US Application US-2015-0225430
 
Associated Publications: J Antibiot (Tokyo). 2014 Jan;67(1):77-83.

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