Evolution has bestowed upon both gram-negative bacteria (GNbac) and the mammalian blood-brain barrier (B-BB) a common, and unique property; a highly restrictive membrane system. These remarkable systems greatly restricts the transport of non-endogenous agents into their interiors. However, when penetration does occur efficient efflux pumps are present to remove these agents back to the external environment. While both of these membranes provide a remarkable protective component to both GNbac and the brain for their survival, they both also represent a major hurdle in the up and coming antibiotic health epidemic and the insurmountable limitations in the treatment of brain cancers and other CNS diseases. There has been numerous advances in the single agent modification of therapeutics that help impart increased penetration across both GNbac and the B-BB. However, the universal applications of these single agent modifications has yet to be translated into a new platform to unlock transport across these complex barriers. Our approach in the aims of developing a new platform for the universal transport of agents of interest across both/either GNbac or the B-BB is based upon peripheral-reversible attachment of small molecules, referred to as chaperone-like small molecules (CLSM). Our current CLSMs are designed to exploit the physicochemical properties unique to GNbac and the B-BB. To be presented is our strategy at the construction of the core scaffolds via enyne metathesis for our first generation CLSMs, efforts at unlocking the additive effects of physicochemical properties through new chemical screening library construction, the merging of said properties onto the core scaffolds, and evaluation. This first generation suite of CLSMs has been shown to impart penetration of doxorubicin by 4% while retaining nearly 65% of its cytotoxicity in our B-BB mimic system and the repurposing of novobiocin (a gram-positive antibiotic) for gram-negative bacteria penetration and cytotoxicity.

Unlocking complex barrier transport via chaperone-like small molecules: A new platform for gram-negative bacteria and blood-brain barrier penetration

2019 Spring National Meeting

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