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Enzyme-Mediated Directional Transport of a Small-Molecule Walker With Chemically Identical Feet.

ABSTRACT: We describe a small-molecule "walker" that uses enzyme catalysis to discriminate between the relative positions of its "feet" on a track and thereby move with net directionality. The bipedal walker has identical carboxylic acid feet, and "steps" along an isotactic hydroxyl-group-derivatized polyether track by the formation/breakage of ester linkages. Lipase AS catalyzes the selective hydrolysis of the rear foot of macrocyclized walkers (an information ratchet mechanism), the rear foot producing an (R)-stereocenter at its point of attachment to the track. If the hydrolyzed foot reattaches to the track in front of the bound foot it forms an (S)-stereocenter, which is resistant to enzymatic hydrolysis. Only macrocyclic walker-track conjugates are efficiently hydrolyzed by the enzyme, leading to high processivity of the walker movement along the track. Conventional chemical reagents promote formation of the ester bonds between the walker and the track. Iterative macrocyclization and hydrolysis reactions lead to 68% of walkers taking two steps directionally along a three-foothold track.

SUBMITTER: Martin CJ

PROVIDER: S-EPMC5618142 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Enzyme-Mediated Directional Transport of a Small-Molecule Walker With Chemically Identical Feet.

Martin Christopher J CJ Lee Alan T L ATL Adams Ralph W RW Leigh David A DA

Journal of the American Chemical Society 20170815 34

We describe a small-molecule "walker" that uses enzyme catalysis to discriminate between the relative positions of its "feet" on a track and thereby move with net directionality. The bipedal walker has identical carboxylic acid feet, and "steps" along an isotactic hydroxyl-group-derivatized polyether track by the formation/breakage of ester linkages. Lipase AS catalyzes the selective hydrolysis of the rear foot of macrocyclized walkers (an information ratchet mechanism), the rear foot producing ...[more]

PMID: 28762738

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Project description:Snakebite remains a significant public health burden globally, disproportionately affecting low-income and impoverished regions of the world. Recently, researchers have begun to focus on the use of small-molecule inhibitors as potential candidates for the neutralisation of key snake venom toxins and as potential field therapies. Bitis vipers represent some of the most medically important as well as frequently encountered snake species in Africa, with a number of species possessing anticoagulant phospholipase A2 (PLA2) toxins that prevent the prothrombinase complex from inducing clot formation. Additionally, species within the genus are known to exert pseudo-procoagulant activity, whereby kallikrein enzymatic toxins cleave fibrinogen to form a weak fibrin clot that rapidly degrades, thereby depleting fibrinogen levels and contributing to the net anticoagulant state. Utilising well-validated coagulation assays measuring time until clot formation, this study addresses the in vitro efficacy of three small molecule enzyme inhibitors (marimastat, prinomastat and varespladib) in neutralising these aforementioned activities. The PLA2 inhibitor varespladib showed the greatest efficacy for the neutralisation of PLA2-driven anticoagulant venom activity, with the metalloproteinase inhibitors prinomastat and marimastat both showing low and highly variable degrees of cross-neutralisation with PLA2 anticoagulant toxicity. However, none of the inhibitors showed efficacy in neutralising the pseudo-procoagulant venom activity exerted by the venom of B. caudalis. Our results highlight the complex nature of snake venoms, for which single-compound treatments will not be universally effective, but combinations might prove highly effective. Despite the limitations of these inhibitors with regards to in vitro kallikrein enzyme pseudo-procoagulant venom activity, our results further support the growing body of literature indicating the potential use of small molecule inhibitors to enhance first-aid treatment of snakebite envenoming, particularly in cases where hospital and thus antivenom treatment is either unavailable or far away.

Dataset Information

Enzyme-Mediated Directional Transport of a Small-Molecule Walker With Chemically Identical Feet.

Publications

Enzyme-Mediated Directional Transport of a Small-Molecule Walker With Chemically Identical Feet.

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