Sulfotyrosine dipeptide: Synthesis and evaluation as HIV-entry inhibitor

Abstract

Human immunodeficiency virus type 1 (HIV-1) is responsible for the worldwide AIDS pandemic. Due to the lack of prophylactic HIV-1 vaccine, drug treatment of the infected patients becomes essential to reduce the viral load and to slow down progression of the disease. Because of drug resistance, finding new antiviral agents is necessary for AIDS drug therapies. The interaction of gp120 and co-receptor (CCR5/CXCR4) mediates the entry of HIV-1 into host cells, which has been increasingly exploited in recent years as the target for new antiviral agents. A conserved co-receptor binding site on gp120 that recognizes sulfotyrosine (sTyr) residues represents a structural target to design novel HIV entry inhibitors. In this work, we developed an efficient synthesis of sulfotyrosine dipeptide and evaluated it as an HIV-1 entry inhibitor.

Keywords: Antiviral therapy; HIV entry inhibitor; Protein sulfation; Sulfopeptide; Sulfotyrosine; Sulfotyrosine dipeptide; gp120.

Figure 1. Neutralization assays

Four compounds were examined in the assay, including sTyr, tyrosine dipeptide (NH₂-Tyr-Tyr-COOH), mono-sulfated tyrosine dipeptide (a mixture of NH₂-sTyr-Tyr-COOH and NH₂-Tyr-sTyr-COOH), and sulfotyrosine dipeptide (NH₂-sTyr-sTyr-COOH). The relative luminescence unit (RLU) of the emitted light from the luciferase reaction was measured in an Illuminometer. Each data point is the average of multiple measurements with standard deviation.

Scheme 1

(a) DCC, TEA, 4:1 CH₃CN:DMF; (b) LiOH, r.t.; (c) SO₃/DMF, 4:1 DMF:pyridine; (d) 9:1 TFA: water, 0 °C.