Parasitology Seminar Series
Title: “Malaria parasite plasmepsins: Not just your father’s old degradative enzymes"
Speaker: Daniel Goldberg, MD, PhD
David M. & Paula L. Kipnis Distinguished Professor Division of Infectious Diseases Department of Medicine, Washington University
Date: Monday, November 4, 2019
Time: 12-1 pm
Lunch with students/speaker, 1:00 p.m. in Hill 111
132 Hill Pavilion
University of Pennsylvania School of Veterinary Medicine
380 S University Avenue, Philadelphia, PA 19104
Abstract: The human malaria parasite Plasmodium falciparum has ten genes that encode aspartic proteases called plasmepsins. Seven of these are expressed in intraerythrocytic parasites. The first four to be studied were the digestive vacuole plasmepsins (plasmepsins I-IV), enzymes involved in the essential process of hemoglobin catabolism. Their characterization provided a basis for designing a large number of antimalarial aspartic protease inhibitors. However, the correlation for these compounds between digestive vacuole plasmepsin inhibition and parasite killing is poor, and the four plasmepsins can be knocked out genetically without fully impairing parasite viability. The digestive vacuole plasmepsins do not appear to be the killing targets of existing inhibitors.
Further work has identified plasmepsin V as an essential membrane-bound ER processing enzyme that licenses effector proteins for export into the host cell. A limitation of this protease as a drug target is that inhibition must be nearly total to have a cellular effect. Plasmepsins IX and X are involved in parasite egress and invasion. Both proteases are processing enzymes. Knockdown of plasmepsin IX leads to a defect in biogenesis of rhoptry invasion organelles. Knockdown of plasmepsin X causes inability to initiate the proteolytic cascade needed for the parasite to get out of its host erythrocyte and to reinvade a new host cell. A number of compounds that were initially investigated as digestive vacuole plasmepsin inhibitors turn out to work by inhibiting these two newly characterized plasmepsins. Defining the essential molecular targets for old antimalarial aspartic protease inhibitors is facilitating progression through the drug development process.
Bio: Daniel Goldberg, MD, PhD did his undergraduate work at Harvard, where he trained with Eugene Kennedy. He was an MD/PhD student at Washington University, doing doctoral work with Stuart Kornfeld. After a residency in Internal Medicine at Brigham and Women’s Hospital in Boston, he did an Infectious Diseases fellowship at Washington University and Postdoctoral work at Rockefeller University with Anthony Cerami. He returned to Washington University to join the faculty in 1990 and is currently David M and Paula L Kipnis Distinguished Professor of Medicine in the Division of Infectious Diseases and Professor of Molecular Microbiology.
Dr. Goldberg’s laboratory works on the biology of intraerythrocytic malaria parasites, particularly with regard to nutrient acquisition, host cell remodeling, egress and identification of new drug targets. His work has been recognized with fellowship in the American Association for the Advancement of Science (AAAS), American Academy of Microbiology (AAM), American Society of Clinical Investigation (ASCI) and Association of American Physicians (AAP). He has been awarded the CC and Alice Wang Award of the American Society for Biochemistry and Molecular Biology.
Please contact Sue Waddington-Pilder (firstname.lastname@example.org) to arrange to speak with Dr. Goldberg.