Tuftsin-AZT conjugate: potential macrophage targeting for AIDS therapy

Abstract

The IgG-derived immunomodulating peptide tuftsin, Thr-Lys-Pro-Arg, is recognized by specific receptors on phagocytic cells, notably macrophages, and is capable of targeting proteins and peptides to these sites. Aiming to target 3'-azido-3'-deoxythymidine (AZT) to HIV-infected macrophages, a conjugate of AZT with tuftsin was synthesized. The AZT-tuftsin chimera possesses the characteristic capacities of its two components. Thus, like AZT, it inhibits reverse transcriptase activity and HIV-antigen expression, and similarly to tuftsin, it stimulates IL-1 release from mouse macrophages and augments the immunogenic function of the cells. Importantly, the conjugate is not cytotoxic to T-cells. The results suggest that the AZT-tuftsin conjugate might have potential use in AIDS therapy.

Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis

“…Tuftsin (threonine-lysine-proline-arginine, TKPR) promotes phagocytic activity for cells of monocytic origin that express tuftsin receptors, such as neutrophils, macrophages and microglia [12,13]. Tuftsin-positive cells are recruited to sites of inflammation, and the avidity and specificity of tuftsin for its receptor are sufficiently strong to enable exploitation of tuftsin for imaging and therapeutic purposes [14-16]. …”

AZT and AZT-monophosphate Prodrugs Incorporating HIV-protease Substrate Fragment: Synthesis and Evaluation as Specific Drug Delivery Systems

“…Thus, zidovudine (AZT) or AZT-MP has been conjugated to a 14-aminoacid peptide (Tamamura et al, 2001) or to bicyclam (Dessolin et al, 1999), which targets the chemokine CXCR-4 co-receptor expressed by the T cells, and to a neoglycoprotein, which targets sugar-recognizing lectins on T-lymphocytes (Molema et al, 1990). In addition, AZT has been conjugated to tuftsin (Fridkin et al, 2005) and associated to colloidal carriers (Lobenberg & Kreuter, 1996) with the aim of targeting macrophages. With regards to targeting the HIV-1 virion itself, conjugation of AZT to oligopeptides binding to the HIV-1 gp120 has also been performed (Shimizu et al, 1995).…”

Molecular Concepts of Macrophage Targeting

“…Tuftsin is a natural macrophage activator tetrapeptide (Thr-Lys-Pro-Arg) which is a part of the Fc-portion of immunoglobulin-G [61]. It has been proposed to be used in conjunction with AZT for targeting HIV-infected macrophages [62].…”