Date of Award

6-2022

Document Type

Open Access

Degree Name

Bachelor of Science

Department

Biochemistry

First Advisor

Lee Pedzisa

Keywords

HIV, co-receptor, host cells, CCR5, Maraviroc

Abstract

The goal of our project is to synthesize a dual CXCR4/CCR5 co-receptor inhibitor to block the entry of HIV into host cells. In the early phase of the HIV-1 replication cycle, HIV-1 binds to host cells through the CD4 protein present on the host cell surface. To infect the cell, HIV-1 requires further interactions that promote fusion of the viral and cellular membranes. This can occur through binding to the chemokine co-receptors such as CXCR4 and CCR5. We are choosing dual inhibition since under selective pressure of a CCR5 antagonist, CXCR4-using strains have been shown to predominate. Through dual inhibition, we want to minimize possible resistance development that could occur when inhibiting only one of the two co-receptors.

Using a computational screen, a compound predicted to bind to both CCR5 and CXCR4 was identified (Hit 1). We established a reaction scheme to synthesize an analog of this compound (target compound 4) through solid phase peptide synthesis. We confirmed the successful synthesis of this compound through LCMS and HPLC.

We also made progress towards synthesizing two analogs of target compound (4) by varying the last Fmoc-phenylalanine. The first analog contained Fmoc-4-fluoro-phenylalanine while the second analog contained Fmoc-4-methoxy-phenylalanine.

Lastly, we ran a docking screen to determine FDA approved compounds that could be repurposed as potential CCR5 inhibitors. In this, 40 compounds were identified to bind CCR5 with a higher affinity than FDA-approved CCR5 inhibitor, Maraviroc.

Download

Included in

Biochemistry Commons

Share

COinS
 

Rights Statement

In Copyright - Educational Use Permitted.