Falcipain

Proteins are all about shape and structure, whether they ensure health or cause disease and death. For postdoctoral student Stephanie Wang, one particular protease — falcipain-2 — remains the subject of intense interest, in large part because of the role it plays in malaria's unrelenting and murderous march through much of the world.

"The malaria-causing parasite uses falcipain to digest hemoglobin from the host's blood and nourish itself." Inhibiting this digestive process will starve and kill the parasite, a goal more easily stated than accomplished. The reason: to inhibit falcipain requires detailed information about its structure and binding sites — information that can only be gained through a process known as X-ray crystallography. This process directs X-rays at a crystalline sample of a protein and records the diffraction pattern on a photographic plate. The pattern of spots plots the structure. Once plotted, it can be modeled in three dimensions by special computer programs. Of particular interest are the binding sites, the places where the molecule connects with other molecules - in key-and-lock fashion — to make different things happen.

Falcipain-2 was discovered in the laboratory of UCSF researcher and infectious disease specialist Phil Rosenthal. His laboratory provides the protein needed for Wang's crystallography efforts. Collaborating with Wang on other parasite proteases is fellow McKerrow postdoc Conor Caffrey, who generates vast amounts of desired proteases by expressing them in bacteria or yeast. "My goal is to screen the proteases and find out where the active sites are on the molecule in order to identify optimal inhibitors that bind to them. I then pass that information on to Stephanie."

As Wang explains, more than one combination of inhibitors is possible at the same binding site, requiring a fastidious and painstaking analysis of the best candidate. "Best" is defined as having the most impact on the disease-causing target and the least consequence for healthy cells, tissue and organs. Delivery and cost are other considerations, a practical matter for this native of China who understands the daily threat posed by infectious disease. "If we find a potential drug that is expensive to produce and difficult to administer, it won't work in the developing world."

Wang and Caffrey appreciate another reality as well. Finding one drug will not be enough. "Monotherapies will lead to drug resistance," Wang explains. "We will need to create cheap drug cocktails, administered orally."

by Jeff Miller