CXCR1CXCR2 Peptide Antagonists

As indicated above, the chemokine N-termi-nus seems to contain a critical recognition site important for receptor binding and activation. The ELR sequence is essential to CXCRl/li-gand interaction and its importance in IL-8 has been established through analog deletion or amino acid substitution within this region (13). Truncation of the first five amino acids in the IL-8 Nt (IL-8[6_72]), or substitution of the first five amino acids with two alanines (IL-gave high affinity antagonists capable of blocking receptor binding, neutrophil chemotaxis, and respiratory burst (282). An N-terminal truncation of GROa demonstrates CXCR2 antagonism; similar changes in PF4

have also been shown to antagonize CXCR2 (283). These NH2-terminally modified analogs had no effect on IL-&stimulated elastase release or superoxide generation, which are responses presumed to be mediated by CXCR1.

A naturally occurring inhibitor of IL-8 (IL-8INH) has been identified in the supernatant of polymorphonuclear leukocytes. This 52-kDa protein blocks 125I-IL-8 binding to the receptor by binding specifically to IL-8. IL-8INH demonstrates in vivo activity by inhibiting neutrophil infiltration to mouse ear (284).

Capped hexapeptides and heptapeptides have also been reported as inhibitors of IL-8. Antileukinate (58)inhibitsthe binding of IL-8 to both receptors and blocks both neutrophil chemotaxis and activation (285). GROa and IL-8 have been shown to be necessary for growth of lung, stomach, and colon adenocarcinomas, and antileukinate will inhibit the binding of GROa to specific receptors on adenocarcinoma cell lines and block proliferation

(286). Antileukinate has also been shown to block Staphylococcal enterotoxin A (SEA)-in-duced neutrophil infiltration into the lung

7.1.4 CXCR1/CXCR2 Small Molecule Antagonists. There are early reports of natural products identified as CXCR1 and CXCR2 antagonists. Extracts from sponge (Dysidea frondosa) provided Frondosins A (59) and C (60) as novel sesquiterpenes (288). Lissoclin

disulfoxide (61) was also extracted from a marine organism, the South African asidian Lis-soclinum (289). All three natural products (59-61) show modest affinity for CXCR2 (Table 4.9). However, similar activity against PKC was also noted, and thus the activity appears to be nonselective.

Table 4.9 Inhibition of CXCRl, CXCR2, and PKCa with Frondosins A and C, and Lissoclin Disulfoxide


CXCR1" Binding

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