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J Am Chem Soc. 2016 Mar 23;138(11):3610-22. doi: 10.1021/jacs.5b12608. Epub 2016 Mar 7.

On-Demand Targeting: Investigating Biology with Proximity-Directed Chemistry.

Author information

1
Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
2
Department of Biochemistry, Weill Cornell Medicine , New York, New York 10065, United States.

Abstract

Proximity enhancement is a central chemical tenet underpinning an exciting suite of small-molecule toolsets that have allowed us to unravel many biological complexities. The leitmotif of this opus is "tethering"-a strategy in which a multifunctional small molecule serves as a template to bring proteins/biomolecules together. Scaffolding approaches have been powerfully applied to control diverse biological outcomes such as protein-protein association, protein stability, activity, and improve imaging capabilities. A new twist on this strategy has recently appeared, in which the small-molecule probe is engineered to unleash controlled amounts of reactive chemical signals within the microenvironment of a target protein. Modification of a specific target elicits a precisely timed and spatially controlled gain-of-function (or dominant loss-of-function) signaling response. Presented herein is a unique personal outlook conceptualizing the powerful proximity-enhanced chemical biology toolsets into two paradigms: "multifunctional scaffolding" versus "on-demand targeting". By addressing the latest advances and challenges in the established yet constantly evolving multifunctional scaffolding strategies as well as in the emerging on-demand precision targeting (and related) systems, this Perspective is aimed at choosing when it is best to employ each of the two strategies, with an emphasis toward further promoting novel applications and discoveries stemming from these innovative chemical biology platforms.

PMID:
26907082
PMCID:
PMC4805449
DOI:
10.1021/jacs.5b12608
[Indexed for MEDLINE]
Free PMC Article

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