Design and Applications of Bifunctional Small Molecules: Why Two Heads Are Better Than One.
Induction of protein--protein interactions is a daunting challenge, but recent studies show promise for small molecules that specifically bring two or more protein molecules together for enhanced or novel biological effect. The first such bifunctional molecules were the rapamycin- and FK506-based "chemical inducers of dimerization", but the field has since expanded with new molecules and new applications in chemical genetics and cell biology. Examples include coumermycin-mediated gyrase B dimerization, proteolysis targeting chimeric molecules (PROTACs), drug hybrids, and strategies for exploiting multivalency in toxin binding and antibody recruitment. This Review discusses these and other advances in the design and use of bifunctional small molecules and potential strategies for future systems.
Corson
Timothy W
TW
Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, Connecticut 06511, USA.
Aberle
Nicholas
N
Crews
Craig M
CM
D019281:Dimerization; D015195:Drug Design; D008024:Ligands; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*
D008024:Ligands; D011506:Proteins