Novel 4,4-Disubstituted Piperidine-Based C–C Chemokine Receptor-5 Inhibitors with High Potency against Human Immunodeficiency Virus-1 and an Improved human Ether-a-go-go Related Gene (hERG) Profile

Normal B-lymphocyte maturation and proliferation are regulated by chemotactic cytokines (chemokines), and genetic polymorphisms in chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1–infected persons were examined for associations of previously described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and CCR2 chemokine receptor gene variants with the risk of B-cell non-Hodgkin’s lymphoma (NHL). The SDF1-3′A chemokine variant, which is carried by 37% of whites and 11% of blacks, was associated with approximate doubling of the NHL risk in heterozygotes and roughly a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3′A/3′A homozygotes and 22 (10%) of 202 SDF1-+/3′A heterozygotes, compared with 24 (5%) of 514 wild-type subjects. The acquired immunodeficiency syndrome (AIDS)-protective chemokine receptor variant CCR5-▵32 was highly protective against NHL, whereas the AIDS-protective variant CCR2-64I had no significant effect. Racial differences in SDF1-3′A frequency may contribute to the lower risk of HIV-1–associated NHL in blacks compared with whites. SDF-1 genotyping of HIV-1–infected patients may identify subgroups warranting enhanced monitoring and targeted interventions to reduce the risk of NHL.

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Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: A mechanism for cellular human immunodeficiency virus 1 infection

Nature Medicine ◽

10.1038/77498 ◽

2000 ◽

Vol 6 (7) ◽

pp. 769-775 ◽

Cited By ~ 370

Author(s):

Matthias Mack ◽

Andrea Kleinschmidt ◽

Hilke Brühl ◽

Christiane Klier ◽

Peter J. Nelson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Chemokine Receptor ◽

Immunodeficiency Virus ◽

Chemokine Receptor Ccr5 ◽

Human Immunodeficiency Virus 1 ◽

Receptor Ccr5

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Decreasing Sensitivity to RANTES (Regulated on Activation, Normally T Cell–Expressed and –Secreted) Neutralization of CC Chemokine Receptor 5–Using, Non–Syncytium‐Inducing Virus Variants in the Course of Human Immunodeficiency Virus Type 1 Infection

The Journal of Infectious Diseases ◽

10.1086/377105 ◽

2003 ◽

Vol 188 (6) ◽

pp. 864-872 ◽

Cited By ~ 61

Author(s):

Fransje A. Koning ◽

David Kwa ◽

Brigitte Boeser‐Nunnink ◽

Jos Dekker ◽

Jose Vingerhoed ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Chemokine Receptor ◽

Cc Chemokine ◽

Immunodeficiency Virus ◽

Cc Chemokine Receptor 5 ◽

Chemokine Receptor 5

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Obstacles and options in the quest for drug candidates against vascular disease

Thrombosis and Haemostasis ◽

10.1160/th10-04-0256 ◽

2010 ◽

Vol 104 (07) ◽

pp. 1-3 ◽

Cited By ~ 3

Author(s):

Christian Weber

Keyword(s):

Metabolic Disease ◽

Human Immunodeficiency Virus ◽

Clinical Trials ◽

Chemokine Receptor ◽

Drug Candidates ◽

Immunodeficiency Virus ◽

Aging Populations ◽

Ccr5 Antagonists ◽

Cc Chemokine Receptor 5 ◽

Human Immunodeficiency Virus 1

Summaryhe difficulties in cardiovascular drug development have been exposed by recent clinical trials, which have uncovered various limitations of promising drug candidates. Yet, the imperative to improve medical treatment of atherosclerosis in aging populations afflicted by metabolic disease remains unbroken. Herein alternatives to metabolically active compounds such as glitazones and torcetrapib are introduced and discussed, namely CC chemokine receptor 5 (CCR5) antagonists recently approved for treatment of patients with human immunodeficiency virus-1, interceptors of proatherogenic chemokine interactions, and actively protective pathways. A combination of different strategies may yield improved safety profiles of these therapeutics.

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