"Zapping the Zipper" might well be the title of researchreported in this week's Science under the more sober rubric"HTLV-1 Tax Protein Stimulation of DNA Binding of bZIPProteins by Enhancing Dimerization."
"What this paper describes," its principal author, Michael Green,told BioWorld, "is a novel mechanism as to how you canstimulate gene expression."
When that gene is working for a virus, especially an oncogenicone, Green said, "what you can do is set up a mechanism-basedassay to look for inhibitors." That's what he and his laboratoryat the University of Massachusetts Program in MolecularMedicine are now doing, in collaboration with a spin-offbiotechnology company, ScripTech Pharmaceuticals Inc. ofCambridge, Mass.
A consortium of five venture-capital concerns foundedScripTech in October 1992 to exploit research by Green andPeter Kim, a protein-folding scientist at Howard HughesMedical Institute in Boston. Its acting chief operating officer,Barry Weinberg, is a partner in the CW Group of New York, thelead investor in the venture. The other VCs are Axcel Partners,Atlas Venture, New Enterprise Association and VenRock.
They have funded ScripTech "with enough money to carry itfor a couple of years," Weinberg, who is now looking for apermanent CEO to assume control of the company, toldBioWorld.
ScripTech's focus, he said, "is to develop drugs PP anti-viral,antibacterial, anti-fungal PP that interfere with gene expressionand are active in the cell nucleus." He added that the company'slead compound interferes with the Rev protein in HIV, and thatScripTech's scientists have already identified sites in bacteriaand fungi that make useful targets because they have nocounterparts in the human organism.
Green's recent work, as reported in the current issue of Science,constitutes the meat of the pending patent that the Universityof Massachusetts has licensed to ScripTech so it can pursueinhibition of the HTLV-1's Tax protein.
"What we discovered," Green explained, "is the mechanism bywhich this oncoprotein transforms cells. And that gives us andScripTech a way to design assays to find inhibitors."
HTLV-1, Green said, "was the first human retrovirus everisolated PP by Robert Gallo and his colleagues some years ago."It causes adult T-cell leukemia, mainly in Japan.
An HTLV-1 gene encodes the Tax protein, which is essential forviral replication. Tax activates transcription of the virus,primarily through the latter's promoter. The cellulartranscription factors involved in the viral genome belong to alarger super family of factors that bind the viral DNA via a so-called basic leucine zipper (b-zip) motif. This motif is associatedwith "some very important cellular oncogenes," Green said.
Like a real zipper, the b-zip DNA-binding motif has twocomponents. One is the zip, consisting of a leucine spaced atevery seven amino acids. Two is the b-for-basic region,comprising such non-acidic amino acids as lysine and arginine,which actually contact the DNA.
During in vitro experiments, Green and his colleagues "foundthat this protein, Tax, promiscuously stimulated the first stepin the DNA-binding activity of any b-zip protein we gave it."The b-zip proteins bind DNA in a two-step reaction: First, theirtwo monomeric molecules homo-dimerize; second, this dimercontacts the DNA directly.
"What we showed is that Tax zips it up better," Green added. "Itstimulates dimer formation, which we think explains why itactivates the viral promoter and makes cells malignant byincreasing the activity of oncoproteins such as jun and fos."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.