James Shorter, Ph.D.
University of Pennsylvania

Jim Shorter graduated with distinction in Biology from Keble College, University of Oxford in 1995. He then joined Graham Warren’s laboratory at the Imperial Cancer Research Fund at Lincoln’s Inn Fields in London (now Cancer Research UK London Research Institute) where he studied the molecular mechanisms of Golgi architecture and inheritance, and received his Ph.D. in Cell Biology from University College London of The University of London in 2000.Jim moved to the United States to continue his studies with Graham Warren between 2000 and 2002 as a Post-Doctoral fellow in the Cell Biology Department of Yale University School of Medicine. In 2002, he joined Susan Lindquist’s laboratory at the Whitehead Institute for Biomedical Research at MIT as a post-doctoral fellow, winning a Charles A. King Trust Post-Doctoral Fellowship. In 2005, he won an American Heart Association Scientist Development Award and became a Senior Research Associate at the Whitehead Institute for Biomedical Research. In April 2007, Jim became an Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania, where he established his own group in the Department of Biochemistry and Biophysics. In the same year he became a member of the editorial advisory panel for The Biochemical Journal and won a NIH Director’s New Innovator Award. In 2009, Jim won an Ellison Medical Foundation New Scholar in Aging Award. In 2010, Jim won a Grand Challenges Explorations Award from the Gates Foundation. In 2012, Jim was selected as the seventeenth recipient of the Michael S. Brown New Investigator Research Award, which recognizes emerging faculty engaged in innovative discoveries. In 2013, Jim was promoted to Associate Professor of Biochemistry and Biophysics with tenure.

Research: We are studying how molecular tweezers might be applied to combat HIV infection. Semen is the main vector for HIV transmission and contains amyloid fibrils that enhance viral infection. Available microbicides that target viral components have proven largely ineffective in preventing sexual virus transmission. In our recent study, we established that CLR01, a ‘molecular tweezer’ specific for lysine and arginine residues, inhibited the formation of infectivity-enhancing seminal amyloids and remodeled preformed fibrils. Moreover, CLR01 abrogated semen-mediated enhancement of viral infection by preventing the formation of virion-amyloid complexes and by directly disrupting the membrane integrity of HIV and other enveloped viruses. Importantly, we established that CLR01 acts by binding to the target lysine and arginine residues rather than by a non-specific, colloidal mechanism. CLR01 counteracts both host factors that may be important for HIV transmission and the pathogen itself. These combined anti-amyloid and antiviral activities make CLR01 a promising topical microbicide for blocking infection by HIV and other sexually transmitted viruses. We are now developing CLR01 variants that more selectively target the amyloid or the virus.

CLR01 is a broad-spectrum inhibitor of enveloped viruses. CLR01 inhibited the infection of human cells by the membrane-enveloped viruses (A) Human cytomegalovirus,  (B) Herpes simplex virus type 2, and (C) Hepatitis-C virus. In contrast, the non-enveloped adenovirus type 5 (D) was unaffected by CLR01. The negative-control derivative CLR03 was ineffective, as expected.