Title: Macrocyclic polyamines inhibit HIV infection by interacting with the cellular HIV co-receptors CXCR4 and CCR5
Authors: Schols, Dominique
Hamal, Sunil
Cui, Li
Huskens, Dana
Aquaro, Stefano
Bell, Thomas #
Issue Date: 24-Sep-2009
Host Document: Retrovirology vol:6 issue:Suppl 2
Conference: Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts location:Montpellier, France date:21-23 September 2009
Article number: P80
Abstract: Background

A number of macrocyclic polyamines and/or their metal complexes are known to have anti-HIV activity. For example, CADA compounds are triazacyclododecanes that specifically down-modulate CD4, the principal cellular receptor for HIV. Bicyclams and their metal complexes act as entry inhibitors by a different mechanism, via specific binding to the cellular co-receptor CXCR4. Manganese(II) complexes of certain penta-azacyclo-pentadecanes are superoxide dismutase mimics and reduce oxidative stress in cells; one such compound, M40401, has been reported to decrease apoptosis in HIV-infected astrocytes.

Materials and methods

By synthesizing and screening various pyridine-fused macrocyclic polyamines, we have discovered several lead compounds that act as HIV entry inhibitors by binding to one or both cellular HIV co-receptors, CXCR4 and CCR5.


One of these new leads is SH06, the manganese(II) complex of a novel ring-fused pentaazacyclopentadecane. SH06 inhibits replication of HIV-1 IIIB and NL4.3 in MT-4 cell cultures with IC50 values of 0.2-0.4 μg/mL and with CC50 (cytotoxicity) of 20 μg/ml. Remarkably, SH06 interacts with both HIV co-receptors CXCR4 and CCR5, according to specific chemokine-induced calcium-signaling assays. SH06 acts as an antagonist toward SDF-1-induced Ca2+-signaling in CXCR4-transfected cells (IC50: 0.3 μg/ml) and inhibits SDF-1-induced chemotaxis of CD4+T cells (IC50: 0.5 μg/ml). However, SH06 acts as an agonist toward CCR5. In addition, the compound also has significant activity (IC50: 0.8-4.9 μg/ml) against several X4 and R5 viruses in PBMCs and monocytes/macrophages.


New macrocyclic polyamines and their manganese complexes have been shown to interact with the HIV co-receptors CXCR4 and CCR5 and to inhibit HIV replication in various cell types. In particular, the manganese complex SH06 showed promising activity against X4 HIV-1, but also against R5 HIV-1. Analogs of this compound are of interest as potential novel chemokine receptor inhibitors and anti-HIV agents.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
# (joint) last author

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