BioWorld International Correspondent

LONDON - A peptide that is found naturally in human blood is capable of preventing the human immunodeficiency virus (HIV-1) from infecting human cells. Understanding just how it does this could lead to a new class of anti-HIV drugs and perhaps even drugs to treat other viruses, too.

In laboratory tests, the peptide could inhibit strains of HIV-1 that were known to be resistant to existing drugs. Chemical alterations to the peptide were able to increase the strength of its antiviral properties by a factor of 200.

Frank Kirchhoff, professor of virology at the University of Ulm in Germany, told BioWorld International: "Although there are now about 20 different drugs approved by the U.S. Food and Drug Administration for the treatment of HIV-1 and AIDS, they all belong to four groups. The emergence of multidrug resistance is an increasing problem, so that there is an urgent need for drugs targeting new regions of the virus, which we hope to develop by further study and modification of our peptides."

Kirchhoff and his collaborators reported their findings in a paper in the April 20 issue of Cell titled: "Discovery and Optimization of a Natural HIV-1 Entry Inhibitor Targeting the gp41 Fusion Peptide".

Scientists have known of the presence in human blood of natural inhibitors of HIV-1 for decades, but it has frequently been difficult to purify or characterize antiviral compounds released from human cells. More recently, researchers, including companies such as IPF Pharmaceuticals GmbH, of Hanover, Germany, have developed the technology for separating peptides from haemofiltrate - the fluid filtered from the blood of patients having kidney dialysis.

Haemofiltrate is available in huge quantities, and contains more than a million different peptides and small proteins, including chemokines, defensins, cytokines and hormones.

When Kirchhoff heard a talk some years ago by Wolf-Georg Forssmann of IPF Pharmaceuticals, who is joint senior author of the Cell paper, he decided that this type of resource would be the perfect way to identify some of the antiviral compounds present in human blood.

He and his colleagues screened a peptide library generated from human haemofiltrate for molecules with antiviral activity. They found that the fraction with the most potent antiviral activity contained a peptide of 20 amino acids. That peptide corresponded to the end of a molecule called alpha-1 antitrypsin, which is a serine protease inhibitor.

The peptide has been called virus-inhibitory peptide, or VIRIP.

After extensive investigations, Kirchhoff and his colleagues established that VIRIP targets a region of HIV-1 called the fusion peptide. Normally, the fusion peptide, which is highly hydrophobic, is hidden in the viral envelope glycoprotein. During the process of infection, the fusion peptide becomes inserted into the membrane of the host cell, acting like an anchor.

"We found that VIRIP binds directly to this region of the viral glycoprotein and most likely blocks its insertion into the host cell membrane," Kirchhoff said. "As a consequence, the viral membrane cannot fuse with the host cell membrane."

The team went on to generate and analyze a large variety of VIRIP variants. "We were surprised that VIRIP was so specific," Kirchhoff said. "We found that if you make it just one amino acid longer or shorter, it completely loses its activity. By changing a few amino acids within it, we were able to increase its antiretroviral potency by two orders of magnitude."

Preclinical studies carried out to date suggested that VIRIP is reasonably stable and non-toxic. The team hopes to progress to Phase I clinical trials by next year.

Kirchhoff hypothesizes that because VIRIP works outside the cell, it may have fewer side effects than other inhibitors that work inside the cell.

So far, the researchers have found it difficult to generate variants of HIV-1 that are resistant to VIRIP. Kirchhoff said: "It is fair to say that it is not very easy for the virus to develop resistance to it, but - given that HIV has so far become resistant to every inhibitor that is available - it would be naïve to think that the virus would not develop resistance to VIRIP, too."

One of the team's goals is to find out if it can improve further on VIRIP's antiviral potency by generating peptides that bind to the HIV-1 fusion protein even better. "In addition," Kirchhoff added, "because peptides need to be injected intravenously, they are not ideal as drugs. In the very long term, it may be possible to use the information on the structure and the contact points between VIRIP and the fusion peptide to generate other antiretroviral drugs that target this region but are not peptides."

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