New Scholar Award in Global Infectious Disease
Michael Jeffrey Root,, M.D., Ph.D.
Thomas Jefferson University

Targeting Viral Entry Using the 5-Helix Protein Design Strategy

Ebola virus (EbV), respiratory syncytial virus (RSV) and human T-cell leukemia virus type 1 (HTLV-1) are serious human pathogens of global importance. Readily spread EbV infection almost always leads to hemorrhagic fever, a devastating illness with mortality rates as high as 85%. RSV is one of the most common causes of severe respiratory tract infections in infants, young children and immunocompromised individuals, often leading to lifelong pulmonary morbidity. HTLV-1 infects over 25 million people worldwide and can lead to chronic and acute forms of adult T-cell leukemia, an extremely debilitating cancer characterized by severe immunodeficiency symptoms, profound neurological deficits and death. At present, therapeutic options to target these viral infections are limited or not available, and antiviral vaccines are only in the earliest preclinical stages of development.

Despite being on distant branches of the viral phylogenetic tree, EbV, RSV, and HTLV-1 appear to share a common entry mechanism: all three viruses contain a fusion protein that folds into a trimer-of-hairpins structure to promote the fusion of the viral and cellular membranes. Formation of the trimer-of-hairpins is an essential step during entry because it enables the close apposition of viral and cellular membranes necessary for fusion. We have recently developed a protein design strategy to disrupt trimer-of-hairpins formation by targeting epitopes on the viral fusion proteins in their prefolded state. The designed proteins, collectively denoted 5-Helix molecules, resemble the trimer-of-hairpins structures but lack one crucial segment corresponding to the targeted eptiope. A 5-Helix molecule based upon the HIV-1 trimer-of-hairpins displays potent, broad-spectrum inhibitory activity. We are currently testing the generalizability of this design strategy to produce inhibitors of EbV, RSV, and HTLV-1. Our experiments will provide insights into the exposure on the viral surface of potential epitopes suitable for the development of antiviral therapeutics and neutralizing antibodies.

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