Proinflammatory cells like lymphocytes and macrophages play a key role in transplant rejection and autoimmune diseases like psoriasis. Finding drugs that keep these cells from accumulating at sites of inflammation is of great interest to Gabriele Weitz-Schmidt, a Senior Research Investigator at the Novartis Institutes for BioMedical Research at Basel, Switzerland. “Proinflammatory cells use adhesion molecules to migrate into tissues where they become activated and injure surrounding tissues,” said Gabriele, “and we would like to stop them from getting in.”
Gabriele was studying an adhesion molecule called leukocyte function-associated antigen-1 (LFA-1) that helps proinflammatory cells stick to the lining of blood vessels, a crucial step in the migration of these cells from the blood into inflamed tissues. “We screened for an LFA-1 inhibitor and out of 100,000 compounds we had one hit – a statin!” said Gabriele. Statins are a class of drugs that lower blood cholesterol levels. No one expected them to inhibit cell adhesion via LFA-1. Gabriele’s team discovered that statins bind to a previously unknown binding site on LFA-1, which she called the L-site. “When the L-site is occupied, LFA-1 is locked in an inactive state that makes it unable to participate in cell adhesion,” she explained.
“We worked closely with structural biologists to characterize molecular interactions at the L-site,” said Gabriele, “which helped us to identify better LFA-1 inhibitors and to advance our understanding of cell adhesion regulation at the molecular level.” Selected LFA-1 inhibitors including a licensing-in product are now in toxicological testing, potential therapeutic indications are being assessed, and the first clinical trials are being planned. “It’s a privilege to work with a highly motivated cross-functional team on a novel therapeutic target and to remain involved as the project is moving to the stage of clinical testing” said Gabriele.
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