F is for Finding Cures

Fighting parasitic diseases has been a career-long quest of UCSF biochemist and parasitologist James McKerrow. But until recently, it has often been a lonely one. Parasitic diseases, such as malaria, trypanosomiasis and schistosomiasis, most often afflict the poor and powerless in the developing world — hardly a tempting market for pharmaceutical companies, which must spend vast sums to develop and test new drugs.

UCSF's newly organized Sandler Center for Basic Research in Parasitic Diseases has been designed to change the chemistry behind this lack of marketplace interest. How? By turning a confederation of laboratories at UCSF into what McKerrow, the director of the Sandler Center, calls a "small drug company."

The confederation of seven "core" laboratories, each with a special expertise, mimics in important ways the private-sector drug development process. Research will move along a continuum from basic research on the origins of disease and drug target discovery to the preclinical development of lead drugs that target parasitic diseases.

This latter stage comprises both laboratory and animal studies. The UCSF difference, McKerrow explains, is that university researchers, who often supply the drug targets to industry and then move on to other projects, will now be doing the preclinical testing of promising anti-parasitic drugs themselves. Says McKerrow, "We will fill the gap that now exists between promising candidates and first-phase clinical trials."

Moreover, in league with non-governmental health organizations both in the US and elsewhere, the Sandler Center may forge production alliances with facilities in other countries. "Once efficacy has been proven in animals, we will need quantities of the drug to take it into clinical trials."

Putting the university in the role normally played by a pharmaceutical company may seem a harrowing prospect to those with a knee-jerk belief in the superiority of the private sector. But as McKerrow notes, many of the tools and techniques used to find, winnow and test potential drug targets — from the pioneering software program known as DOCK, which calculates and displays in three dimensions how potential drugs might attach to target molecules, to a method for generating large amounts of different peptides — were first developed or refined at UCSF.

In fact, this entrepreneurial spirit, combined with a strong sense of social responsibility, has rallied new investigators to the cause, where they have joined not only McKerrow, but other stalwarts like malaria expert Phil Rosenthal. The core list includes, in addition to McKerrow (biochemistry and molecular biology of parasitic diseases), Irwin Kuntz and Fred Cohen (computer-based drug design), Joe DeRisi and Erin O'Shea (robotics and genomics), Robert Fletterick (X-ray crystallography), Kip Guy (synthetic chemistry), and Les Benet (pharmacokinetics and drug metabolism).

Moreover, as a way to test the drug-development concept, McKerrow and his colleagues are moving ahead with plans for a clinical trial of a compound that shows promise against an enzyme essential to the development of Chagas disease. Triggered by the bite of an infected insect called the "kissing bug," which deposits a tiny one-celled organism called a trypanosome into the bloodstream, Chagas disease is the primary cause of acute and chronic heart disease in Latin America. An estimated 17 million people are affected.

Says McKerrow, "We found this compound as the result of collaboration. That is the culture at UCSF; we share information across disciplines."

If successful against Chagas, the pattern will be repeated against other parasitic diseases, transforming the fulcrum of laboratories into a one-of-a-kind drug discovery and testing center. Two grant programs — one to encourage scientists both within and outside UCSF to develop promising ideas in the field and the other to train scientists from countries in which parasitic diseases are endemic — also are planned. For now, McKerrow is certain of one thing. "There is nothing else like this place in the world."

by Jeff Miller