A potential next-generation anti-AIDS drug is in the makingbetween the National Cancer Institute of National Institutes ofHealth and the Sanyo-Kokusaku Pulp Co. (SKP) of Tokyo.

SKP and NCI retrovirologists are co-inventors of a U.S. patentapplication titled "Anti-Viral Compounds and Their Uses."

These compounds are a series of eight halogen-substitutionnucleoside analogs, chemical kin to, but different from, thecurrent anti-AIDS prescription drugs, AZT and ddI(dideoxyinosine). Like their cousins, the nucleoside analogs areintended to inhibit the human immunodeficiency virus (HIV),particularly in infected patients who have developed resistanceto AZT and ddI.

A 60-day advance notice in the Federal Register on Feb. 16signaled that the NIH's Office of Technology Transfer proposesto grant SKP an exclusive, royalty-bearing license to thepending patent, conditional on the Japanese company's"expeditiously finding a sublicensee capable of clinicaldevelopment." NCI and SKP signed a cooperative research anddevelopment agreement (CRADA) last September coveringdevelopment of the anti-AIDS analogs for human therapy.

NIH will definitively award the license unless itsannouncement in the Register elicits a legally valid objection byApril 16.

"SKP designed and supervised synthesis of the eight 6-halogen-substituted 2',3'-dideoxypurine ribofuranosides," said HiroakiMitsuya, who heads NCI's Experimental Retrovirology Section."The company then submitted the compounds to us forelucidating their mechanism of action and properties," he toldBioWorld. "We identified their potent anti-viral activity andtheir lipophilicity."

That molecular affinity for lipids defines the compounds'specific potential as future AIDS drugs. Because of their lipid-loving nature, they can penetrate the blood-brain barrier toattack HIV in the central nervous system (CNS), where it mighthole up even before it produces overt clinical symptoms in itsvictims.

So, Mitsuya surmises, "HIV in the CNS may serve as a principalreservoir of the virus in the whole body."

He added, "Thus, the capability of these anti-viral agents topenetrate into the CNS may constitute an important feature oftherapeutics against HIV infection."

He points out that the lipophilicity of ddI is generally low bycomparison with the analogs. AZT penetrates the CNS better,but six of SKP's eight purine nucleosides have still higherlipophilic coefficients.

By substituting a halogen atom (chlorine or iodine) for anoxygen, one "confers substantial lipophilicity on these newanalogs, but they appear to exert their anti-viral activity onlyupon conversion to ddI or ddG (dideoxyguanosine)."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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