A strategy to target the “undruggables”

Drug designers have successfully created many protein drugs to battle human disease. But most proteins cannot cross cell membranes, so in general these drugs lock on to molecular targets studding the cell surface that indirectly affect processes inside the cell. But many important targets, including protein complexes, RNA, and DNA, reside inside the cell and have largely been deemed “undruggable” by protein drugs.

In the July 27 issue of Chemistry & Biology, a team of scientists led by Alanna Schepartz, Ph.D., the Milton Harris ’29 Ph.D. Professor of Chemistry, describe a previously unknown molecular signal that helps proteins enter cells and reach the cell interior. The proteins enter via endosomes, small sacs pinched off from the cell membrane, and the newly found signal triggers their release from the endosomal sac.

“We are very keen to understand how this release signal works, as it may allow researchers to engineer molecules to follow a prescribed pathway into cells,” says Schepartz, also director of the Yale Chemical Biology Institute and senior author of the paper.