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Irreversible Inactivation of HIV-1 and SARS-CoV-2 by Targeting Metastable Virus Spike Proteins
Start Date: 6/18/2021Start Time: 10:00 AM
End Date: 6/18/2021End Time: 12:00 PM
Event Description
BIOMED PhD Research Proposal
Irreversible Inactivation of HIV-1 and SARS-CoV-2 by Targeting Metastable Virus Spike Proteins

Aakansha Nangarlia, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Irwin Chaiken, PhD
Professor of Biochemistry and Molecular Biology
College of Medicine
Drexel University

Almost four decades ago, the HIV-1 pandemic swept across human populations, infecting 60 million people and causing over 25 million deaths globally. Today, HIV-1 is one of the leading causes of death in the world. The highly active antiretroviral therapy (HAART) has allowed us to prolong our patients' lives and control the disease's transmission, but it is no cure. In order to find a cure for HIV 1 and eradicate it, drugs need to target both HIV-1 viruses and infected cells. Seeing this as an unmet need, the Chaiken lab has devised HIV-1 envelope-targeting irreversible inactivators (EIs) capable of doing just that. These EIs can target the HIV-1 envelope protein, gp120, and cause self-destruction of the HIV-1 envelope in infected cells and viruses. Their unique modes of action make them one-of-a-kind in the market. The compounds include macrocyclic peptide triazoles (cPTs)/ macrocyclic peptide triazole thiols (cPTTs), small CD4-mimetic dual-action lytic inactivators (DLIs), and lectin dual-action lytic inactivators (Lectin-DLIs). Each of these compounds has a unique mode of action, but all are capable of causing irreversible inactivation. These findings have built the foundation for the development of potent HIV-1 inactivators and allowed us to expand our understanding of the mechanism of HIV-1 envelope transformation during infection. The progress leading to developing various EI class inactivators guided the aims of this project. The project will focus on the investigation of mechanism by which the two classes of EI inactivators, cPTs/cPTTs and DLIs, cause irreversible inactivation of HIV-1 and on identifying and designing the next therapeutic lead EIs for HIV-1 treatment.

At the onset of the COVID-19 pandemic, we saw the structural similarities between HIV-1 and SARS-CoV-2. Like HIV-1, the envelope protein of SARS-CoV-2 is critical in viral infection and production. We decided to test our hypothesis of whether EIs can cause irreversible inactivation of SARS-CoV-2 viruses, like that observed with HIV-1, by either disrupting the intrinsic metastability of the spike or spike aggregation. Thus, providing therapeutic leads for COVID-19 treatment. Therefore, the last part of the project will focus on identifying EIs capable of causing irreversible inactivation of SARS-CoV-2 viruses and identifying their mechanism of action.

Overall, the results from this project will set the foundation for the development and advancement of novel potent entry inhibitors for HIV and COVID-19 treatment. Additionally, the results will help advance our understanding of the structural mechanism that an envelope spike undergoes upon viral entry.
Contact Information:
Name: Natalia Broz
Aakansha Nangarlia
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