New Approach for Inhibition of HIV Entry: Modifying CD4 Binding Sites by Thiolated Pyrimidine Derivatives

Abstract

Thiolated pyrimidine derivatives have been synthetized and their antiretroviral effect against human immunodeficiency virus type 1 (HIV-1IIIB) and HIV-1 chimeric pseudovirions have been quantitatively determined in cell-based viral infectivity assays including syncytium inhibition assay as well as a single-cycle viral infection assay on HeLaCD4-LTR/ß-gal cells. Pseudotype virions prepared bearing HIV-1 envelope preference for CCR5 coreceptor, CXCR4 coreceptor or for both, respectively, with a HIV-1 core containing luciferase reporter gene were able to infect susceptible cells but are replication defective so unable to replicate in the cells . Data indicate that thiolated pyrimidine derivatives inhibited effectively virally induced cell fusion in vitro as well as infectivity of primary HIV-1IIIB strain and HIV-1 pseudovirions using chemokine receptors CCR5 or CXCR4 or both for virus entry a dose dependent manner. Inhibition was selective, depended on the pseudovirus coreceptor preference. Our results suggest that some of these sulfur containing pyrimidines interact with redoxactive -SH groups required for successful HIV entry, including a redox active disulfide in the CD4 molecule as well as -SH groups in HIV viral envelope gp120. This mode of action is unique representing a new class of potential HIV entry inhibitors.

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

“…introduced some thiolated pyrimidine derivatives that interact with redox active SH groups required for successful HIV‐1 entry. In vitro experimental data show that these compounds can effectively inhibit infectivity of primary HIV‐1 IIIB strain and both HIV‐1 R5‐ and X4‐tropic pseudovirions and virally induced cell fusion …”

“…In vitro experimental data show that these compounds can effectively inhibit infectivity of primary HIV-1 IIIB strain and both HIV-1 R5-and X4-tropic pseudovirions and virally induced cell fusion. [35] Signal peptides (SP) are attached to some of the newly synthesized type 1 transmembrane proteins such as cell-surface CD4 receptors. They help translocation of the nascent proteins from endoplasmic reticulum during translation to the lumen and then to the cell membrane.…”

Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment

“…to prevent HIV entry by interacting with redox-active thiol groups on both CD4 and gp120 that are paramount for HIV entry in vitro, 54 although more work is required to establish clinical viability of these compounds.…”