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Also discussed at the ACS symposium was a fundamental study of CCR5 receptor binding carried out recently by Tatjana Dragic, now at the department of microbiology and immunology of Albert Einstein College of Medicine; professor John P. Moore, now at the department of microbiology and immunology at Weill Medical College of Cornell University; Thomas P. Sakmar of Howard Hughes Medical Institute and the laboratory of molecular biology and biochemistry at Rockefeller University; and coworkers [Proc. Natl. Acad. Sci. USA, 97, 5639 (2000)]. THE PURPOSE of the study was to map small-molecule binding domains on CCR5, Sakmar explained. This was done by using site-directed mutagenesis to look at mutations that prevent the receptor from being a drug target of a small molecule. "We looked for mutants that affected the ability of TAK-779 to bind to the receptor," Sakmar says. "Then we mapped the locations of the mutants onto a hypothetical model of the receptor and tried to determine where the small molecule binds—with the idea that from this you could get some insights into designing better or more specific molecules." BICYCLAMS De Clercq and coworkers discovered the CXCR4 inhibitors AMD-3100 and AMD-7049. TAK-779, and by analogy probably other CCR5 inhibitors like SCH-351125, interact with the seven-helix transmembrane domain of the CCR5 coreceptor. The PNAS study suggested that TAK-779 binds primarily within a cavity between transmembrane helices 1, 2, 3, and 7, close to the receptor's extracellular surface boundary. "We intend to use the same strategy to map the binding sites of other of the small molecules that have anti-HIV activity," Sakmar says. Thanks to Sakmar and coworkers, "we're beginning to get a picture of what the CCR5 receptor might look like and beginning to make at least some speculations about how compounds are interacting with the CCR5 receptor," Clader says. "That's the type of thing that is really going to facilitate research in this area." |
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