Nordic Life Science 1
CLINICAL TRIALS SCIENCE ARTICLE OF THE QUARTER Th
e atomic model of CVB3 Nancy in complex with compound 17 based on the cryo-EM density shows the position of the drug at an interprotomer site, located between adjacent VP1 chains (gray and blue) and VP3 (red). REFERENCE ABDELNABI R, GERAETS JA, MA Y, MIRABELLI C, FLATT JW, DOMANSKA A, DELANG L, JOCHMANS D, KUMAR TA, JAYAPRAKASH V, SINHA BN, LEYSSEN P, BUTCHER SJ, NEYTS J. A NOVEL DRUGGABLE INTERPROTOMER POCKET IN THE CAPSID OF RHINO- AND ENTEROVIRUSES. PLOS BIOLOGY, 2019; 17 (6): E3000281. All our studies gave complementary data so it’s a nice basic research result.” The data also suggest a mechanism for viral inhibition. The viruses have a stable conformation when they go from one host to another, for example when we pick up cold viruses from contaminated surfaces. To infect new cells, the viral capsid must change its structure. “The viruses are dynamic,” Butcher says. “But when you put the drug into the surface pocket, it’s like supergluing the virus so now it can’t expand.” Inhibitors seem to stabilize the capsid, preventing transitions that allow release of viral RNA for replication. From the starting compound, the researchers generated more potent and broad-spectrum analogs. The work of tailoring and testing these compounds continues, Butcher says. “We can probably hit many more viruses with 86 NORDICLIFESCIENCE.ORG similar molecules.” She notes that resistant mutations are already known, so capsidbinding drugs will probably need to be part of combination therapies that also target polymerases, proteases, and other key viral enzymes. “We also found areas that the virus can’t mutate,” she says. These regions that are critical for viral replication provide clues about more drug targets. he new class of antiviral compounds has clinical potential, but Butcher’s group focuses on the basic research, continuing their structural studies on viral conformational changes. “Our new compound prevents a transition that occurs across the capsid,” she says, “so we’re finding ways to recapitulate and model what happens during viral infection of cells to find other sites to put the superglue.” NLS ILLUSTRATION RANA ABDELNABI JAMES A. GERAETS, JOHAN NEYTS