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 account for a 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 (Scheme 1). We completed the synthesis of compound 4 and we confirmed the addition of the first three amino acids (Fmoc-phenylalanine, Fmoc-proline and Fmoc-phenylalanine) through LC-MS. Additionally, the addition of the first and third amino acids (Fmoc-phenylalanine and Fmoc-phenylalanine) was also confirmed through HPLC. Lastly, the synthesis of the final compound (target compound 4) was confirmed through LC-MS.
At the moment, we are synthesizing two analogs of target compound (4) by varying the last Fmoc-phenylalanine. The first analog will contain Fmoc-4-fluoro-phenylalanine while the second analog will contain Fmoc-4-methoxy-phenylalanine.
Before the time of presentation, we plan to use our established methodology to synthesize more analogs and evaluate them for biological activity. The goal of synthesizing analogs is to optimize CXCR4/CCR5 dual inhibition