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Macrocyclic polyamines inhibit HIV infection by interacting with the cellular HIV co-receptors CXCR4 and CCR5
Retrovirology volume 6, Article number: P80 (2009)
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.
Results
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.
Conclusion
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.
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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Schols, D., Hamal, S., Cui, L. et al. Macrocyclic polyamines inhibit HIV infection by interacting with the cellular HIV co-receptors CXCR4 and CCR5. Retrovirology 6, P80 (2009). https://doi.org/10.1186/1742-4690-6-S2-P80
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Keywords
- Manganese Complex
- Entry Inhibitor
- Macrocyclic Polyamine
- Complex SH06
- Chemokine Receptor Inhibitor
