Michael Farzan, PhD
Department of Microbiology and Molecular Genetics, Harvard Medical School
VIRAL ENTRY AND ANTI-VIRAL STRATEGIES Viral Receptors; HIV Therapy; Dengue Virus; SARS; Ebola Virus
Undertake translational studies geared toward the development of novel peptide mimetic inhibitors of HlV binding to its cell surface receptor, modeled after the CD4 and CCR5 HIV receptor/co-receptor; study HIV host defense mechanisms.
The research on viral receptors and novel inhibitors of viral entry into cells by the lab has significant commercial potential, making this laboratory an attractive candidate for industry partnerships. The worldwide scope of AIDS and HIV infection is immense, and the pandemic shows no signs of abating. Over 25 million deaths have been attributable to HIV disease. Although new cocktails of drugs have had a dramatic positive effect in lowering virus titer and extending survival in the Westernized world, the morbidity and mortality associated with AIDS remains a major health issue. Since no vaccine appears on the horizon, less toxic treatments are urgently needed, and the work on new peptide mimetics by the lab shows great promise as an adjunct therapy for compromising the ability of the virus to infect host cells. These molecules have been designed based on extensive research into the binding dynamics of HIV to cell-surface receptors, and are effective in blocking HIV entry. This is a unique opportunity for a corporate partner to support further preclinical studies that may lead to more potent and less toxic treatments.
Other projects in the laboratory also have commercial applicability, including identification of the cell surface receptor(s) for Flaviviruses such as Dengue virus. Determining the membrane receptors for these viruses should facilitate new therapeutic approaches to combat this class of virus. The studies that aim to develop new therapeutics for Ebola virus and New World hemorrhagic fever arenaviruses also address critical unmet medical and veterinary needs.
Current Research Interests
- Explore the use of double mimetic therapy for blocking HIV entry into cells
- Extend studies on the role of tyrosine sulfation in HIV contacts with the cell surface
- Develop new mimetics that block Ebola virus entry; although outbreaks of Ebola infection in humans have been contained so far, infection results in a high mortality rate in humans and animals, as evidenced by the decimation of the gorilla population in regions such as the Congo
- Investigate antibody-mediated approaches for combating New World hemorrhagic fever arenaviruses
- Perform biochemical experiments to identify the cell-surface receptor(s) for members of the Flavivirus family such as Dengue virus, which can precipitate a deadly hemorrhagic fever; uncovering the identity of the receptor may lead to new treatments and vaccines
- Study molecular aspects of Dengue hemorrhagic fever
Dr. Farzan’s laboratory has investigated the biochemical mechanisms of viral entry into target cells, focusing on identifying and characterizing the cell surface receptors and corresponding viral binding domains that mediate viral entry, and then using these data to design novel antagonists of viral infection. The lab has made important contributions to our knowledge concerning the cell surface receptors/co-receptors for HIV (gp120/CCR5), SARS coronavirus (ACE2), and the New World hemorrhagic fever arenaviruses (transferrin receptor 1). They have studied in depth the HIV co-receptor CCR5, identifying the region responsible for viral binding, and have shown that sulfated tyrosine residues in CCR5 are indispensable for viral entry. Subsequently, they performed elegant proof-of-concept experiments for employing tyrosine-sulfated peptides as novel antagonists of HIV infection, thus demonstrating that small rationale-based peptides have the potential to curb HIV infection. Recent studies have also shed light on structural aspects of transferrin receptor 1 that confer susceptibility for arenavirus transmission to humans, even though these viruses have evolved to infect rodent hosts. The lab was responsible for identifying ACE2 as the cell surface receptor for the SARS virus, and have collaborated with fellow Harvard investigator Dr. Stephen Harrison in delineating the structural features of the receptor binding domain present on the SARS spike protein that promotes interaction with the cell surface receptor, laying the foundation for novel vaccine approaches.