NIH awards Schiffer $7.9 million to attack drug resistance

New approach to drug design focus of program project grant

By Sandra Gray

UMass Medical School Communications

October 20, 2014
  Celia Schiffer, PhD
  Celia Schiffer, PhD

Deadly diseases including HIV, hepatitis C, tuberculosis and cancer can quickly become resistant to even the most effective drugs. With a new $7.9 million program project grant from the National Institute of General Medical Sciences, Celia Schiffer, PhD, hopes to better understand the complex processes by which diseases rapidly develop resistance to drugs.

“Right now drug resistance isn’t part of the drug design process; it is more of an afterthought, which is very costly to society financially and, ultimately, in human health” said Dr. Schiffer, professor of biochemistry & molecular pharmacology, and founder and director of the Institute for Drug Resistance at UMass Medical School.

“Understanding the mechanisms of resistance will allow us to use the knowledge in drug design from the get-go, instead of playing catch-up after resistance has developed.”

With the project program grant Interdependency of Drug Resistance Evolution and Drug Design, Schiffer and colleagues will identify common pathways by which resistance occurs and devise drug design strategies for developing potent inhibitors that are more robust  against resistance.

Drug resistance occurs when a drug’s target, such as HIV-protease, which Schiffer has extensively investigated, through rapid evolution maintains its activity, and a drug that previously blocked its activity no longer works. “Disrupting the drug target’s activity is necessary but not sufficient for developing a robust drug that avoids resistance,” she said. “Modern drug design fails by ignoring the details of the drug target’s activity.”

The new grant leverages Schiffer’s previous 10-year, $16 million program project grant Targeting ensembles of drug resistant HIV proteases. Initially awarded in 2002, the grant explored how resistance to current HIV-protease inhibitors occurs, and developed and implemented a strategy for avoiding resistance by creating novel potent inhibitors.

That research created what is, in essence, the perfect case study for the new grant’s focus on finding common pathways and mechanisms of drug resistance.

“In the new project, our team will use and develop cutting-edge technology to follow the pathways of drug resistance selection, to elucidate the molecular basis for their interdependent patterns and incorporate these mechanisms into drug design strategies,” said Schiffer. “Together we will make inroads into tackling drug resistance that would be impossible for any of us to individually achieve.”

The Interdependency of Drug Resistance Evolution and Drug Design program led by Celia Schiffer, PhD, comprises three projects conducted by multiple investigators at several institutions in addition to UMass Medical School.

Project 1: The Structural and Dynamic Basis for the Interdependence of Drug Resistance
Celia Schiffer, PhD, professor of biochemistry & molecular pharmacology, UMass Medical School, project lead

Nese Kurt-Yilmaz, PhD, research assistant professor of biochemistry & molecular pharmacology, UMass Medical School
Rieko Ishima, PhD, associate professor of structural biology, University of Pittsburgh School of Medicine

Project 2: Tracking the Evolution of Drug Resistance for Highly Potent HIV Protease Inhibitors
Ronald Swanstrom, PhD, the Charles J. Postelle Distinguished Professor of biochemistry & biophysics, University of North Carolina School of Medicine, project lead

Daniel Bolon, PhD, associate professor of biochemistry & molecular pharmacology, UMass Medical School
Jeremy Luban, MD, the David L. Freelander Memorial Professor in HIV/AIDS Research and professor of molecular medicine, UMass Medical School

Project 3: Integration of Structural and Dynamic Aspects of Drug Resistance into Drug Design
Woody Sherman, PhD, vice president of applications science, Schrödinger, LLC, project lead

These projects are supported by two cores at UMMS:

Organic Synthesis and Enzymatic Assays
Akbar Ali, PhD, research associate professor of biochemistry & molecular pharmacology, UMass Medical School, core lead

Konstantin Zeldovich, PhD, assistant professor of biochemistry & molecular pharmacology and bioinformatics & integrative biology, UMass Medical School, core lead

Related links on UMassMedNow:
Expert’s Corner: Celia Schiffer, PhD, on drug resistance
Djade Soumana awarded NIH grant and HOPE Scholarship: Schiffer lab member strives to reduce disparities in hepatitis C treatment
New initiative to build culture of drug development entrepreneurship

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