In a proof of principle experiment published earlier this year, Gestwicki and collaborators at Amplyx and Stanford created a long-lasting version of a protease inhibitor used to treat HIV. These drugs typically have a short half-life because they are easily broken down by liver enzymes. So they must be given with a second drug, ritonavir, that inhibits the function of those metabolizing enzymes. However, because the same enzymes are needed to metabolize other foreign molecules in the body, ritonavir can have toxic side effects. “This raises the possibility of avoiding the use of ritonavir for HIV proteases,” says Mitchell Mutz, chief scientific officer at Amplyx.
“It looks quite promising,” says Daryl Drummond, senior director of liposome discovery at Merrimack Pharmaceuticals, in San Francisco, of the protease inhibitor research. “This is more or less a slow release and sustained delivery system.” However, Drummond says it’s not yet clear how broadly applicable the technology will be or how attaching these structures to drugs will affect their toxicity.
Amplyx will initially focus on anti-infective drugs, many of which have short half-lives. The startup is partnering with an unnamed pharmaceutical company and has already developed a new version of the antibiotic carbapenem. That drug must be infused three to four times a day, making it expensive to administer. “Attaching our molecule to help the antibiotic bind to FKBP protein, we were able to show it helps increase its time in circulation,” says Mutz.
While pharmaceutical companies routinely screen and modify candidate molecules to improve half-lives and other pharmacological properties, Crabtree says Amplyx’s approach is much more directed. “We can work through it in a way that is more predictable than semirandom modifications that are used to improve half-life and stability,” he says.
Gestwicki says he hopes that studying biologically derived drugs might provide additional clues to better drug design. “Maybe natural products have types of chemical functionalities that give them improved pharmacological characteristics,” he says. “Maybe we can study them and figure out what those features are and install them into synthetic molecules.”