Citation
Morales, Maryann (2025) Metal Binding to Nsp1, a SARS-CoV-2 protein. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/z9m9-yn02. https://resolver.caltech.edu/CaltechTHESIS:05302025-004839918
Abstract
The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the need for novel antiviral strategies beyond vaccines. A key virulence factor in SARS-CoV-2 is nonstructural protein 1 (Nsp1), which suppresses host immune responses by degrading mRNA, inhibiting nuclear export, and binding to the 40S ribosomal subunit to block host translation. Its intrinsically disordered C-terminal domain complicates structure-based drug design, prompting exploration of alternative approaches.
This work investigates the use of transition metal coordination to target disordered regions of Nsp1. Copper(II) and cobalt(III) complexes were examined for their ability to bind histidine residues—particularly H165, critical for ribosome interaction. Biophysical techniques, including fluorescence spectroscopy, EPR, and ⁵⁹Co NMR, along with computational modeling, were used to characterize binding to Nsp1-derived peptides and the full-length protein.
Cu(II) displayed pH-dependent coordination through histidine and backbone amides, while oxidized Co(III) complexes formed stable, substitution-inert interactions. Multi-site binding and distinct kinetic profiles were observed. In vitro translation assays showed that metal complexes can affect translation, though selective inhibition of Nsp1 remains challenging.Overall, this work provides a foundation for targeting disordered viral proteins using coordination chemistry.
Item Type: | Thesis (Dissertation (Ph.D.)) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Subject Keywords: | SARS-CoV-2, Nsp1, Copper(II), Cobalt(III) | |||||||||
Degree Grantor: | California Institute of Technology | |||||||||
Division: | Chemistry and Chemical Engineering | |||||||||
Major Option: | Chemistry | |||||||||
Thesis Availability: | Public (worldwide access) | |||||||||
Research Advisor(s): |
| |||||||||
Thesis Committee: |
| |||||||||
Defense Date: | 8 May 2025 | |||||||||
Funders: |
| |||||||||
Record Number: | CaltechTHESIS:05302025-004839918 | |||||||||
Persistent URL: | https://resolver.caltech.edu/CaltechTHESIS:05302025-004839918 | |||||||||
DOI: | 10.7907/z9m9-yn02 | |||||||||
Related URLs: |
| |||||||||
ORCID: |
| |||||||||
Default Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | |||||||||
ID Code: | 17303 | |||||||||
Collection: | CaltechTHESIS | |||||||||
Deposited By: | Maryann Morales | |||||||||
Deposited On: | 30 May 2025 23:36 | |||||||||
Last Modified: | 06 Jun 2025 22:14 |
Thesis Files
![]() |
PDF (Redacted thesis - ch. 4-5 omitted)
- Final Version
See Usage Policy. 3MB |
Repository Staff Only: item control page