Scripps investigators ID a key player in disarming chemotherapy

Multidrug resistance to the chemotherapies in wide use today is a lethal problem. As patients stop responding to drugs, they become increasingly vulnerable to a deadly assault. Now investigators at The Scripps Research Institute say they have illuminated a key protein that plays a big role in promoting drug resistance, offering a new approach for investigators designing the next generation of new and improved cancer therapies that won't eventually be disarmed.

Using electron microscopes, the scientists in the study were able to watch as an ABC transporter called P-glycoprotein (P-gp) changes shape, promoting drug resistance. They also studied another transporter protein called MsbA, which is found in bacteria.

P-gp plays an important role in catching and expelling toxins from cells. But the Scripps team watched P-gp also spit out chemotherapies. Using the powerful microscopes, they were able to watch how ligands bind to P-gp, triggering changes in the structure of the protein. And they observed that stopping multidrug resistance is likely to be very challenging, as the ligands leave spaces for other molecules to bind to the transporter.

The next phase of this study will look at how they can design molecules that can steer clear of P-gp, making it possible to equip new drugs that won't get caught in the net and expelled.

"This information will help us design better molecules to inhibit or evade multidrug resistance," said TSRI Associate Professor Qinghai Zhang, a senior author of both studies.

- here's the release

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