Embedded in the coat protein of the AIDS virus lurks a short stretchof amino acids that acts like an antiviral agent. This does not meanthat HIV-1 carries in its peptide baggage the seeds of its owndestruction.DP178, as researchers at Duke University call the virus-inhibitingmolecule they've discovered, seems more an artifact of peptidecomputer-modeling than a verified component of the viralenvelope. But it has potential.Physical biochemist Carl Wild and his co-workers at the DukeCenter for AIDS Research, came upon DP-178 (standing for "DukePeptide"), which they synthesized and characterized structurallyand biologically. What they found they reported in the current issueof the Proceedings of the National Academy of Sciences (PNAS),dated Oct. 11.Their report, of which Wild is first author, and center directorThomas Matthews, senior author, bears the title: "Peptidescorresponding to a predictive a-helical domain of humanimmunodeficiency virus type 1 gp41 are potent inhibitors of virusinfection."But only in HIV-1; the peptide does not act on the rare HIV-2strain."DP-178," the PNAS paper reported, "consistently blocked 100percent of virus-mediated cell-cell fusion . . . and gave anapproximately 10 times reduction in infectious titer of cell-freevirus . . ." It added that this inhibitory activity occurred at levels farbelow those at which cytotoxicity showed up."Because the concentrations of DP-178 at which we see biologicalactivity are so low," Wild told BioWorld Today, "There's a chancethat the material itself could actually _ as a peptide _ function, ormaybe show some promise as a therapeutic. But peptides bythemselves," Wild added, "have a very poor track recordfunctioning as therapeutic agents."There are two schools of thought, Wild said, as to why HIV-1 - ofall viruses -should harbor within its structure a sequence capable ofcutting short its own infectivity."One school," he continued, "holds that the interaction we'relooking at is authentic, taking place in the native virus. The othercontends that it's just coincidental, an interaction that happens totake place between these two regions of gp41, only when they'remodeled as peptides."The transmembrane gp-41 has components that lie both within andupon the retroviral surface. Gp120, an antigen much favored byAIDS vaccine architects, is associated with the surface of gp41.Together, they form the protein complex that envelops HIV-1.Peptide modeling is the approach the Duke investigators are takingto explore the structure and function of HIV-1. This means that theyresort to software algorithms _ function-oriented mathematicalprojections of biochemical sequences - to predict secondary, ortwo-dimensional, structural components, based on primary amino-acid sequence."Regions of the viral envelope that contain alpha-helical or coiled-coil structures," Wild explained, "have a propensity to form suchpredictive structures, and the software is pretty good."AIDS Virus's Double-WhammyHIV-1 infection comes in one of two modes, by which the virushijacks its target T cells. In one scenario, the cell-free viral particlessimply penetrate the cell and take over its replication machinery. Inan ensuing drama, infected cells expressing viral envelope fuse withand infect uninfected neighboring target cells."That either/or infectivity," Wild said, "is one of the moreinteresting aspects of our paper; the fact that we see a difference inthe inhibitory concentrations of DP-178, with respect to these twomodes of infection."He added, "If you think about these processes of viral infection, theimplications for development of antivirals and therapeutics arecertainly there."Even more interesting to Wild _ and potentially to virus victims aswell as virus researchers _ is DP-178's residence on the mosthighly conserved regions of HIV-1's envelope sequence. That is,the peptide can hold its own whenever the virus changes its spots. Itis this genetic drift that makes the AIDS virus so elusive topharmaceutical or immunological attack.Wild suggests that DP-178's resistance to drift arises because "Eventhough you see sequence variation in the envelope among differentvirus isolates, the inhibitory activity of this material doesn't seem tobe a function of a particular viral isolate."He explained: "If you look at the transmembrane protein in anumber of retroviruses, especially other enveloped viruses,including non-retroviruses such as rabies and influenza, there's anamazing amount of sequence homology." These look-alike amino-acid domains, Wild said, are particularly frequent "in regions thatpredict certain types of structures, such as the alpha-helical ones.These fusion proteins tend to lie quite close to the membrane-spanning domain, from which DP-178 derives."I don't think," he added, "that the material we're working with, theHIV-1 peptide, as it's configured now, has a potential to inhibitother viruses. But analogous regions, modeled from other virusesmay act as inhibitors in those viral systems."Making HIV-1 Fall On Its SwordOne such virus that plays the same game as HIV-1 is influenza. Inthe laboratory of Peter Kim at the Whitehead Institute inCambridge, Mass., protein biochemist Chavela Carr, has shown theeffect. That peptide, Carr told BioWorld Today, "is in the sameregion of the flu virus hemagglutinin. In both flu and HIV-1, itshows an alpha-helical conformation, and forms a coiled coil."An alpha-helix, she explained, "is the first coil. The second consistsof alpha-helices wound around themselves, like a rope. In viralglycoprotein (gp) conformations, there are three coiled coils."Her flu peptide, she said, "offered an explanation we'd been waitingfor a long time: How does that fusion peptide get to the cell'smembrane, 100 A away?" The coiled coil provided an answer: "Itextends the fusion peptide up to the top of the molecule, where thecell membrane is."Carr added, "So what we're hoping, and what people are very busytrying to show, is that the HIV-1 envelope protein, gp41 plusgp120, uses the same mechanism."The most important thing," she emphasized, "that could be easilymissed here, is that if these proteins undergo the conformationalchange prematurely, before reaching the target cell, they areinactivated. So if we had agents that would target this protein tostabilize that coiled coil, or trigger a conformational change in itearly, those viruses would not be able to enter their host cell, andwe could thus prevent infection."Wild commented that "We've identified an agent, this DP-178peptide, which actually does what Carr predicted, It abrogates thefunction of the coiled coil by some sort of interaction, and would beuseful as far as therapeutics are concerned." n

-- David N. Leff Science Editor

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