Wednesday, April 9, 2014

Smash and grab

Published in Drug Discovery News

LA JOLLA, Calif.—Scripps Research Institute scientists have devised two highly specific methods to create new drugs, one that flings a single atom as a wrecking ball and another that can find therapy targets in tiny folds of microRNA.
A paper published in Nature in March describes research by Scripps chemistry professor Jin-Quan Yu that builds on his earlier groundbreaking development of using a weak chemical bond in molecule frameworks previously thought to be an obstacle, instead turning it into a powerful advantage when building drug compounds.
To attach function groups to chemical frameworks, a C-H bond must be broken—and it must be a specific, and possibly different, one for each potential intended attachment option.
“The best way to make a molecule is to replace a C-H bond directly,” Yu tells DDNews.
Some C-H bonds, though, don’t react, and are far away from attachment points of potential catalysts, rendering them difficult to break. With previous methods, “you cannot make certain types of molecules,” Yu says.
Yu’s insight, which he has been developing since 2002 at the University of Cambridge, was that he could install nitrile groups—weak connections that were dismissed in the past as hurting the structure of a framework—and use that weakness to facilitate the swinging of a catalyst across the molecular distance to a remote C-H bond, allowing it to be broken.
At that point, just as with other broken C-H bonds, functional groups that are building blocks for drugs can be attached, Yu said.
He originally published about the technique for what is called “meta” C-H activation inNature in 2012; the most recent paper has both simplified the process and allowed it to be applied more specifically to targeted C-H bonds.
“The key is to tune the shape of the template to create a subtle bias towards the targeted carbon hydrogen bond,” Yu said in Scripps’s announcement of the paper. “At the same time the template’s movement towards the target site has to be exploited effectively by a super-reactive catalyst.”
The chemical reagent involved will be available through Bristol-Myers Squibb’s catalog for order by laboratories, so that other researchers may use it in their own work, including targeting compounds common in drug discovery, such as tetrahydroquinoline, benzooxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines. “All these are commonly used in medicinal chemistry either as final drug compounds or intermediate compounds from which the final compounds are made,” Yu notes.
And in the future, he expects to further refine the technique so that the nitrile groups can be used catalytically, rather than needing to be installed and later removed.
The other approach, developed by Matthew Disney at the Scripps Florida campus, also inverts a standard method of searching for binding opportunities, this time in microRNA folds. Where previously researchers had to take RNA structures and do high-throughput screenings to find binding opportunities, Disney has built a database of potential types of bonds between RNAs and small-molecule function groups.
Then, by comparing given RNA sequences—not structures—to the database, Disney’s method can pinpoint possible opportunities. Only then does attention turn to the structures themselves, he tells DDNews: “Once we identify these interacting partners, could we find them … and drug it?”
Every disease has a relation to RNA, he said, because proteins play key roles in the process.
“If there’s some toxic protein … we can potentially target the RNA that makes that protein,” Disney says. (Alternately, if a disease causes too little of a protein to be produced, his technique can boost production.)
As a test case, and proof of concept, Disney and his team identified a druggable target—and its corresponding drug—in MiR-96 microRNA, which is believed to delay cell death by obstructing apoptosis, a natural cell-death process that begins when cells begin to grow in ways that are otherwise uncontrollable.
“People think that RNA can’t be drugged with a small molecule,” Disney says, but his approach proves that belief wrong. And it offers the prospect of very tightly targeting cells, in a way much narrower than the broad targeting approach taken today, where non-disease-related cells are also affected by therapies.
Next, Disney will go after diseases without current cures, such as Ebola, as well as orphan diseases that may need therapeutic-research attention.
While resistance to microRNA-targeting drugs is possible, Disney said his approach would help respond: “If resistance were to happen, and the RNA structure were to change,” then they could go back to the database and find binding matches for the new structure, he says.