New NIH funding awarded to the Department of Pharmaceutical Chemistry in 2011
Friday, April 13, 2012
New research support awarded to the UCSF School of Pharmacy by the National Institutes of Health during the 2011 fiscal year included these on-going projects by faculty in the Department of Pharmaceutical Chemistry:
Precisely targeting malaria parasites with drugs
Adam Renslo, PhD
- Associate director of chemistry for the department-housed Small Molecule Discovery Center
- Awarded $207,625 from the National Institute of Allergy and Infectious Diseases as part of a two-year $442,688 research grant
Renslo is developing a new drug delivery technology to more precisely target the parasites that cause malaria, which is responsible for close to a million preventable deaths worldwide each year.
In malaria, parasites invade red blood cells and digest hemoglobin, the protein that carries oxygen through the body, thus generating significant concentrations of ferrous iron in the form of unbound heme in their digestive compartments. Renslo’s delivery system specifically targets that type of iron, which is extremely rare in healthy cells.
The system uses a derivative of a new class of synthetic anti-malarial drugs (now in late-stage clinical trials) with a chemical structure that breaks apart in the presence of the free heme. This fragmentation yields anti-malarial effects of its own, but in Renslo’s system it also severs a chemical linkage, which only then releases and activates a second drug inside the parasite.
Using this NIH funding, the approach was successfully demonstrated in mice. The selective drug delivery cured the infection and also reduced the animal’s overall exposure to the partner drug, notably improving its safety and reducing side effects.
The research team, which includes Matthew Bogyo, PhD, faculty member at Stanford University School of Medicine, is now seeking to refine the delivery system, including chemically simplifying it to make it cheaper to produce, with the goal of eventually testing it in humans.
Renslo’s work on targeted drug delivery potentially enables the use of effective drugs that would otherwise be too toxic.
Directed protein-chopping to dissect cellular self-destruction
James Wells, PhD
- Professor and chair
- Awarded $285,442 by the National Institute of General Medical Sciences as part of a four-year $1.1 million research grant
Wells’ latest NIH-funded project augments his lab’s focus on apoptosis, which is the healthy self-destruction of damaged cells that fails to occur in cancers. He is applying technologies developed or co-developed by his lab to dissect the process.
Normally, a sub-group of protein-cleaving protease enzymes called caspases spur the final steps of cell demolition by cutting apart as many as 1,000 different types of proteins.
To determine which targets or networks of targets are most important amid this implosion of simultaneous protein-chopping, Wells developed methods to cleave specific targets using an engineered enzyme called the SNIPer. Another technique tags and identifies the products of those chopping events.
Wells will isolate and analyze the effect of caspase cleavage on three cellular sub-systems:
- Enzymes that cleave and repair DNA
- Enzymes that promote and halt cell replication
- The proteasome, a complex in the cell that normally destroys caspases and other selected cellular proteins, thus acting as a brake on caspase-induced apoptosis
Wells’ precise dissection of apoptosis should help scientists identify weak points in the cell to design new drugs to treat the uncontrolled proliferation of cancer cells.
Image credit (Wells): © majedphoto.com
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