ABSTRACT
C-C chemokine receptor 5 (CCR5), one of the major co-receptors of HIV-1, can mediate the fusion of HIV-1 to cell membranes. CCR5 antagonists can bind to CCR5 and cause conformational changes in CCR5, thus blocking HIV-1 infection. Several small molecule CCR5 antagonists with strong activity and good tolerance have been screened and entered the clinical trials. With the widespread use of CCR5 antagonists, drug resistance has gradually emerged. There are many reports about of drug-related failure in vivo and in vitro. Therefore, this review summarizes the mechanism of CCR5-mediated HIV-1 infection, the research progress in maraviroc and other CCR5 antagonists which have entered clinical trials and their drug resistance.
ABSTRACT
AIM:To study the effects of antagonistic peptides binding specifically with the first and second extracellular loops (ECL1 and ECL2) of C-C chemokine receptor 5 (CCR5) on the colitis rats induced by trinitrobenzenesulfonic acid (TNBS) and the mechanisms.METHODS:The colitis model of SD rats was induced by TNBS (100 mg/kg).The effects of 2 antagonistic peptides at different doses (ECL1:25, 35 and 45 mg/kg;ECL2:15, 25 and 35 mg/kg) on the model rats including the changes of disease activity index (DAI), colon macroscopic damage index (CMDI) and histological grading were observed.The mRNA and protein expression levels of TNF-α and COX-2 in the colonic mucosa were detected by real-time PCR and Western blot, respectively.RESULTS:Compared with model group, the changes of DAI, CMDI and histopathological injury of the rats treated with ECL2 antagonistic peptide HY at an appropriate dose were significantly reduced (P<0.05), and the protein and mRNA expression levels of TNF-α and COX-2 were significantly decreased (P<0.05).However, the effects of ECL1 antagonistic peptide GH on all scores and the expression levels of TNF-α and COX-2 were not obvious.CONCLUSION:ECL2 antagonistic peptide HY relieves TNBS-induced colitis in SD rats via down-regulating the expressions of TNF-α and COX-2 in the colonic mucosa, while the effect of ECL1 antagonist peptide GH was not obvious.