Isis Pharmaceuticals Inc. has discovered a new anti-HIVcompound that binds to the V3 loop of the HIV membraneprotein gp120, thereby inhibiting HIV infection of cells.

The compound, ISIS 5320, was discovered through Isis'combinatorial drug-discovery program. The Carlsbad, Calif.,company announced Wednesday that it has begun preclinicaltesting of the drug, the first to emerge from its combinatorialstrategy. ISIS 5320 is described in an article by JacquelineWyatt of Isis et al in the February issue of the Proceedings ofthe National Academy of Sciences.

Isis explained that "combinatorial" refers to "the creation oflarge libraries of novel new molecules based on randomcombinations of single unit chemicals." A combinatorial libraryproduces a pool of novel compounds, ranging from a fewthousand to many orders of magnitude. Researchers screen thecompounds for drug activities and then use "deconvolution"techniques to identify the active substance in the library anddetermine its structure.

Isis (NASDAQ:ISIP) said its most advanced program is syntheticunrandomization of randomized fragments (SURF), whichinvolves screening subsets of an oligomer library. ISIS 5320was identified from a library consisting of phosphorothioateoligonucleotides. The compound consists of four chains of theoligomer bound together in a "sulfur box" structure.

ISIS 5320 "interferes with the ability of HIV to fuse with themembrane of the target cell and therefore, to enter that cell,"Isis said. "By the same mechanism, ISIS 5320 prevents thedirect transmission of HIV from an infected cell to anuninfected cell."

Isis has been focusing on identifying improved oligonucleotidechemistries for antisense drug development. ISIS 5320 is notan antisense drug. The company has two antisense drugs inclinicals, ISIS 2105, which is in Phase II for treatment ofgenital warts, and ISIS 2922, which is in Phase I/II fortreatment of retinitis in people with AIDS. Isis also has fourdrugs in preclinical development. --Brenda Sandburg

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