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Targeting Fusion Proteins of HIV-1 and SARS-CoV-2

Citation

Jette, Claudia A. (2022) Targeting Fusion Proteins of HIV-1 and SARS-CoV-2. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/pxa2-dy41. https://resolver.caltech.edu/CaltechThesis:04282022-192922044

Abstract

Viruses are disease-causing pathogenic agents that require host cells to replicate. Fusion of host and viral membranes is critical for the lifecycle of enveloped viruses. Studying viral fusion proteins can allow us to better understand how they shape immune responses and inform the design of therapeutics such as drugs, monoclonal antibodies, and vaccines. This thesis discusses two approaches to targeting two fusion proteins: Env from HIV-1 and S from SARS-CoV-2. The first chapter of this thesis is an introduction to viruses with a specific focus on HIV-1 CD4 mimetic drugs and antibodies against SARS-CoV-2. It discusses the architecture of these viruses and fusion proteins and how small molecules, peptides, and antibodies can target these proteins successfully to treat and prevent disease. In addition, a brief overview is included of the techniques involved in structural biology and how it has informed the study of viruses. For the interested reader, chapter 2 contains a review article that serves as a more in-depth introduction for both viruses as well as how the use of structural biology has informed the study of viral surface proteins and neutralizing antibody responses to them. The subsequent chapters provide a body of work divided into two parts. The first part in chapter 3 involves a study on conformational changes induced in the HIV-1 Env protein by CD4-mimemtic drugs using single particle cryo-EM. The second part encompassing chapters 4 and 5 includes two studies on antibodies isolated from convalescent COVID-19 donors. The former involves classification of antibody responses to the SARS-CoV-2 S receptor-binding domain (RBD). The latter discusses an anti-RBD antibody class that binds to a conserved epitope on the RBD and shows cross-binding and cross-neutralization to other coronaviruses in the sarbecovirus subgenus.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:structural biology, viruses, HIV-1, SARS-CoV-2, COVID-19, antibody, small molecule, peptide, cryo-EM, X-ray crystallography, protein
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biochemistry and Molecular Biophysics
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Bjorkman, Pamela J.
Group:COVID-19
Thesis Committee:
  • Clemons, William M. (chair)
  • Voorhees, Rebecca M.
  • Baltimore, David L.
  • Bjorkman, Pamela J.
Defense Date:6 April 2022
Record Number:CaltechThesis:04282022-192922044
Persistent URL:https://resolver.caltech.edu/CaltechThesis:04282022-192922044
DOI:10.7907/pxa2-dy41
Related URLs:
URLURL TypeDescription
http://www.doi.org/10.1038/s41467-021-21816-xDOIArticle adapted for Chapter 3
http://www.doi.org/10.1038/s41586-020-2852-1DOIArticle adapted for Chapter 4
http://www.doi.org/10.1016/j.celrep.2021.109760DOIArticle adapted for Chapter 5
http://www.doi.org/10.3390/v13102106DOIArticle adapted for Chapter 2
ORCID:
AuthorORCID
Jette, Claudia A.0000-0002-5085-8027
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14565
Collection:CaltechTHESIS
Deposited By: Claudia Jette
Deposited On:03 May 2022 20:35
Last Modified:10 May 2022 17:08

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