Undergraduate Honors Thesis

 

A Potential Improved Anti-HIV Drug: Using a Bivalent Design to Increase Specificity and Potency Public Deposited

https://scholar.colorado.edu/concern/undergraduate_honors_theses/6395w7459
Abstract
  • In this thesis, the synthesis of a potentially improved HIV entry inhibitor is presented. HIV has infected millions of people, and yet there is no fully effective treatment for the infection and the subsequent, high mortality disease AIDS. This is due in large part to the virus’s rapid development of resistance to any drug used to treat the infection. The best way to combat this is to use multiple drugs with different inhibition targets and so prevent the virus from developing resistance. In order to contribute to the effective treatment of HIV infection, it is therefore important to develop new classes of inhibitors. One promising recent advance is the development of entry inhibitors, which inhibit the human surface receptor CCR5 and prevent HIV from binding and entering the cell. However, the Pfizer drug Maraviroc is the only approved inhibitor in this class and it has extensive side effects due to imperfect specificity. To improve both the specificity and binding affinity, we proposed to create a bivalent inhibitor from Maraviroc and a specifically glycosylated CCL5. CCL5 is a natural chemokine that also binds to CCR5. It has also been studied as an HIV treatment, although it suffers from large side effects as well, due to causing extended inflammation and tissue damage. Our lab extensively studied the effect of different glycosylation patterns on CCL5 and found that unwanted properties of the protein could be diminished by a specific glycan in one of the two positions. This new glycoform of CCL5, combined with the advantages of a bivalent design with Maraviroc, should create an inhibitor that is both more specific and more potent. Our lab will soon test this new inhibitor; however, this thesis focuses on the design and synthesis of a Maraviroc analog, modified to include a “linker” chain, which will link the two halves of the inhibitor together.
Creator
Date Awarded
  • 2017-01-01
Academic Affiliation
Advisor
Committee Member
Granting Institution
Subject
Last Modified
  • 2019-12-02
Resource Type
Rights Statement
Language

Relationships

In Collection:

Items