Science

Dengue fever fusion proteins analogous to those in influenza, HIV

Last Updated: 2004-01-21 12:58:19 -0400 (Reuters Health)

By Karla Gale

NEW YORK (Reuters Health) - Two different types of viral fusion protein interactions with host cells share important mechanistic features, investigators report in the January 22nd issue of Nature.

The upshot may be that the concept behind the new HIV fusion protein inhibitor Fuzeon could be applied to the design of drugs to treat other viral infections, including dengue fever and hepatitis C, co-investigator Dr. Stephen C. Harrison told Reuters Health.

Dr. Harrison and Yorgo Modis of Harvard Medical School, and researchers at Hawaii Biotech, Inc. in Aiea, Hawaii, used crystallography and electron microscopy to characterize the "fusion loops" of the dengue fever virus, which insert into the target membrane, ultimately leading to the fusion pore that allows viral RNA to enter the host cell.

"We show the molecular contortions that flavivirus undergoes" to bring the two membranes into close proximity and catalyze fusion, Dr. Harrison explained.

His group describes class I fusion proteins, found in measles virus, HIV, and Ebola, as alpha-helical, coiled assemblies derived from a cleaved, single-chain precursor, which create the central structural element of the fusion machinery. Class II fusion proteins, they observed, possess a beta-sheet-type structure that forms an internal hydrophobic fusion loop, which then attaches to the host cell membrane.

The results suggest two different, perhaps complementary strategies to treat viral infections, the authors note: interfering with the fusion protein transition when it first attaches to the host cell, and blocking the completion of the irreversible conformational change, as does the HIV drug Fuzeon.

In the same issue of Nature, Dr. Felix A. Rey, in Gif-sur-Yvette, France, and his associates describe similar analyses of the fusion loops of Semliki Forest virus, which is of the same family as rubella virus. The fusion protein resembled the class II protein of dengue fever.

Referring to the paper by Dr. Rey et al, Dr. Harrison said, "Once evolution found a solution for something, it tended to re-use it. As a result, the range of problems that we need to face to develop other fusion inhibitors are probably fewer than we originally thought."

He hopes that by identifying small, drug-like molecules, researchers can devise assays that will lead to the discovery of clinically useful drugs that do the same thing for other viral infections as Fuzeon does for HIV.

Nature 2004;427:313-325.