Science Editor

Most anti-infectives are small molecules. But peptides also are part of the host defense against infection, a fact that has not been lost on researchers.

For example, Fuzeon (enfuvirtide), developed by Morrisville, N.C.-based Trimeris Inc., is a synthetic peptide that inhibits viral fusion. Peptides are being tested against a variety of other viruses, as well, and last week scientists reported in the Oct. 4, 2006, Journal of Virology that a peptide that is able to block herpes simplex infection also is effective against several influenza strains, including the much-feared H5N1 bird flu.

Intriguingly, though the antiviral peptide described in the paper works against both herpes simplex and influenza, it appears to do so by different mechanisms. For that matter, the peptide seems to work differently against herpes simplex depending on its concentration: "At high concentrations, it was viricidal," senior author Stacey Schultz-Cherry told BioWorld Today. "At lower concentrations, it blocks entry."

For influenza, too, the peptide appears to block entry of the virus into cells, but it does so by blocking its interaction with hemagglutinin, an influenza virus surface protein that does not exist on herpes simplex virus. Hemagglutinin and neuraminidase are the two influenza virus proteins that are critical for influenza virus entry into host cells. But Schultz-Cherry said that the peptide is "a small piece of a completely normal cellular protein" that has "no similarity to either viral protein or its receptor."

Instead, it is part of the receptor for fibroblast growth factor, "a portion of the FGF molecule that had been described to help other proteins cross membranes," Schultz-Cherry said.

In cell culture, the peptide inhibited viral replication and cell death by blocking the interaction of the viral hemagglutinin with its receptor.

In vivo, virus that was pretreated with EB peptide was completely unable to infect mice. While pretreating the virus obviously is not a direct model of the clinical situation, when mice were treated with EB peptide post-infection, the peptide's effects were comparable to that of the antiviral rimantadine. Schultz-Cherry said that her team's efforts were focused on defining the basic molecular mechanisms of how the peptide works, rather than trying to mimic possible clinical situations: "We hope that it pans out down the road, but this is still very basic research."

The 3-dimensional structure does not appear to be terribly important for the anti-infective activity of the peptides; in fact, "you don't really think of something that short as having much of a structure," Schultz-Cherry said. She added that the investigators are searching for the minimal requirements for anti-influenza activity "as we speak," and so far, the sequence appears to be the most critical determinant of whether a given peptide will be effective. That wasn't the case for control peptides, including a peptide that consisted of the same amino acids as the EB peptide, but in a different order. The authors concluded that "EB's antiviral activity may be sequence specific and not simply an interaction based upon charge or hydrophobic interactions."

Antibacterial peptides, too, were the subject of some interesting science last week. In a paper to be published in the Proceedings of the National Academy of Sciences but now available online, researchers showed that by replacing one amino acid with its enantiomer, or mirror image, and attaching a fatty acid, they could construct both antibacterial and antifungal peptides that only were four amino acids long. There, too, structure does not appear to be critical for the activity of the short peptides; the authors wrote that "the sequence of the peptidic moiety and the length of the aliphatic acid determine their spectra of antimicrobial activity."