Researchers receive $10.1 million grant
A new grant from the National Institute of Health may help University researchers come closer to a cure for the HIV virus.
The NIH awarded the $10.1 million grant to the Department of Chemistry and Chemical Biology professors and Center for Advanced Biotechnology and Medicine researchers Edward Arnold, Joseph Marcotrigiano, Roger Jones and Ronald Levy earlier this month.
The researchers work with structure-based drug design in their laboratories on Busch campus. Their method examines how drugs interact with proteins, said Joe Bauman, a post-doctorate at the CABM.
At the center, Bauman said his lab group screens small molecules to develop new compounds that can inhibit the effect of a disease.
Anti-HIV research was one of the first applications of structure-based drug design. The idea is to attack its proteins responsible for replication — and particularly reverse transcriptase and HIV protease, Arnold said.
Reverse transcriptase converts viral RNA to DNA, said Dishaben V. Patel, a graduate student at the Ernesto Mario School of Pharmacy who works at the CABM. Viral DNA eventually infects the host.
Arnold said his team and the late Dr. Paul Janssen of Janssen Pharmaceuticals have already developed two FDA-approved drugs that targeted reverse transcriptase, a protein in the HIV virus that makes it difficult to fight.
“While the drugs worked against most strains of HIV, resistance did occur,” he said. “The virus can change and lose the ability to be blocked by a given drug.”
With the new funding, the team hopes to better attack the issue of resistance, he said.
HIV protease, meanwhile, makes the replication of the DNA possible, Marcotrigiano said. While the CABM focuses on reverse transcriptase, the researchers’ partners at the Scripps Research Institute in La Jolla, Calif., study HIV protease.
This cooperative effort will hopefully lead to faster discovery of more effective drugs. Steve Tuske, a research associate at the CABM, said he examines how drugs interact with each other.
To create an effective drug, the center must know how individual drugs interact with each other, Tuske said. That is a key part of structure-based drug design.
But before the researchers can test any drugs, they must first synthesize HIV’s proteins, Marcotrigiano said. Once they produce the proteins in HIV, they can study them in isolation.
“[Anti-viral] drugs must be made from a combination of different drugs for different proteins that knock down replication,” Marcotrigiano said.
At Marcotrigiano’s laboratory, he and University alumna Jillian Whidby work on protein synthesis. The two developed a new way that allowed them to produce a lot of challenging and difficult proteins that have not been done anywhere else, Marcotrigiano said.
“Making proteins is very difficult, but you can’t really observe structural biological systems [like virus structures] without them,” he said.
They have already found cost-effective ways to produce many proteins that allow researchers to build models necessary for structure-based drug design, he said.
“That will be our most important contribution to the grant,” Whidby said.
Marcotrigiano said researchers have found the individual parts of the HIV virus, but have yet to figure out how the domains fit together.
“Unfortunately, there are just too many missing pieces from the HIV structural puzzle,” Marcotrigiano said. “This is a largely unexplored area.”
This is not a problem just for HIV, but also for bacterial infections and cancer, Arnold said.
“Some of the kind of things that we learn through research in one system has implications for broader disease problems,” he said.
Whidby said the researchers kept coming to Marcotrigiano because he could make the proteins in new ways.
“It’s important to think outside of the box and come up with new ways to produce them — otherwise we can’t study them in isolation,” she said.
Arnold said despite the challenges, new technology will help the researchers make advances toward better, more cost-effective drugs.
He said research gives us special insights into many things in nature, human disease and biology in general.
“It is challenging,” he said. “A lot of scientific discipline involves creativity. Each person brings their own training, their own personality, to the problem.”