Chemokine Antagonists

Kledal TN, Rosenkilde MM, Coulin F, et al. A broad-spectrum chemokine antagonist encoded by Kaposi s sarcoma-associated herpesvirus. Science 1997 277 1656-9. 

Vassalli G, Simeoni E, Li JP, Fleury S. Lentiviral gene transfer of the chemokine antagonist RANTES 9-68 prolongs heart graft survival. Transplantation 2006 81 240-246. 

Anders HJ, Frink M, Linde Y, et al. CC chemokine ligand 5/RANTES chemokine antagonists aggravate glomerulonephritis despite reduction of glomerular leukocyte infiltration. J Immunol 2003 170 5658-5666. 

Gong JH, Yan R, Waterfield JD, Clark-Lewis I. Post-onset inhibition of murine arthritis using combined chemokine antagonist therapy. Rheumatology (Oxford) 2004 43(1) 39 12. 

Eisner J, Petering H, Hochstetter R, et al. The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3. Eur J Immunol 1997 27(ll) 2892-2898. 

Damon, I., Murphy, P. M., and Moss, B. (1998). Broad spectrum chemokine antagonistic activity of a human poxvirus chemokine homolog. Proc. Natl Acad. Sci. USA 95, 6403-6407. 

Here we provide the basic methods we use to study chemokine-receptor trafficking. These methods have been used in conjunction with chemokines and chemokine antagonists, and with other agents (e.g., phorbol esters) that can induce receptor endocytosis. In the following protocols, we refer only to the use of chemokines. We use the operational terms endocytosis and recycling to avoid alternative expressions such as down-modulation or down-regulation, desensitization, and resensitization, which may be used to reflect the functional state of the receptor or cell. 

Antibodies against chemokines or chemokine antagonists are injected 30 min before each intranasal Ova-challenge, either ip, in a vol of 100 pL, or intranasally in a vol of 50 pL, or intratracheally in a volume of 10 pL... 

Table 1 Selected 3,4-dichlorophenoxy-l-piperidinyl experimental agents and their corresponding mass spectra. All experimental agents were effective as CCRj /R3 chemokine antagonists using the calcium flux [Ca2+]i assay. H NMR for products and intermediates provided by the author...

Piperidine amines, (III), prepared by Thom (3), V-ureidoalkyl-piperidines, (IV), prepared by Ko (4), and bipiperidine derivatives, (V), prepared by Rigby (5) were effective as CCRj/CCRj chemokine antagonists and used in treating asthma and related allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis. 

Thiazol-2(3H)-ylidene derivatives, (VI), prepared by Fujiwara (6) were effective as CCR /CCR3 chemokine antagonists and used to induce an immediate therapeutic response for patients suffering from atopic asthma and bronchial asthma. 

Many of the published chemokine antagonists have a basic nitrogen as a common feature, and it is interesting to speculate how this might serve as an important recognition element. As noted earlier, the protonated nitro-... 

Jones, S. A., Dewald, B., Clark-Lewis, I., and Baggiolini, M. (1997). Chemokine antagonists that discriminate between interleukin-8 receptors. Selective blockers of CXCR2. J. Biol. Chem. Ill, 16166-16169. 

Another potentially useful direction in therapeutics is to develop the viral chemokine antagonists and scavengers reviewed above, which may be best suited as topical agents or single administration agents for acute inflammation, such as occurs after angioplasty. 

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