The Second National Conference on Human Retroviruses andRelated Infections next Monday will hear about a front-running drugcandidate in the race to curb a critical HIV enzyme.

Virologist George Painter heads the project at Burroughs-WellcomeCo. to develop the HIV protease inhibitor VX-478. He will describethe compound as the smallest molecule now contending to introducea new generation of anti-AIDS therapeutics, and report on itspreclinical results in Washington.

VX stands for Vertex Pharmaceuticals Inc., of Cambridge, Mass. InDecember 1993, Vertex and Wellcome, of Research Triangle Park,N.C., signed a $42-million research and development agreement tobring orally active protease inhibitors to clinical trials and to market.(See BioWorld Today, Dec. 17, 1993, p. 1.)

Like many other pharmaceutical and biotechnology companies,Vertex has been working for several years on putting together acompound to attack the AIDS virus at a different Achilles' heel thancurrent HIV drugs such as AZT , ddi and ddc, which inhibitretroviral transcription.

That alternative target of opportunity in HIV's armor is HIVprotease. Vertex Chief Scientific Officer and Senior Vice PresidentVicki Sato explained that HIV protease is "an enzyme that processesthe viral gag gene, which is essential to viral replication andmaturation. Without it," Sato told BioWorld Today, "the virusremains non-infective."

Today's issue of the biweekly Journal of the American ChemicalSociety (JACS) carries a paper by seven Vertex scientists titled"Crystal structure of HIV-1 protease in complex with VX-478, apotent and orally bioavailable inhibitor of the enzyme."

Its authors describe how the company used structure-based drugdesign to tailor-make a molecule that would block HIV protease'scatalytic activity by plugging the enzyme's active site. Specifically,VX-478 occupies a cleft in the two aspartase proteases that empowerHIV-1 replication inside an infected cell. That viral enzyme is notfound in the host cell itself, principal author Manuel Navia toldBioWorld Today.

"The work on VX-478," Sato said, "was guided by a detailedunderstanding of the atom-by-atom structure of the HIV proteaseenzyme. "Navia, senior crystallographer at Vertex," she observed,"was the first person to solve the X-ray structure of HIV protease,before he came to the company."

Competing firms, among them Hoffmann-La Roche Inc., of Nutley,N.J., also are creating HIV protease inhibitors, of creditable efficacyin vitro. "The problem has been," Navia told BioWorld Today, "thatthose inhibitors have done that at the cost of being very large."

He explained, "When you put large molecules into the blood, theyare subject to being cleared from the circulation."

Vertex researchers analyzed the molecular weight of all 5,687marketed drugs that are administered orally and systemically. Theirweights spread along a bell-shaped curve. Roche, Navia pointed out,"has a compound that at this point is the most advanced HIVprotease inhibitor. Its molecular weight is about 680 Daltons. Ours,purposefully designed to be small, weighs in at 550 Daltons."

Its smaller size enhances solubility, hence oral bioavailability, aswell as having other advantages, he said, adding, "This compound isthe lowest molecular-weight inhibitor of HIV protease currently inclinical development."

Vertex chemist Roger Tung, a co-author of today's JACS paper, toldBioWorld Today, "We have completed essentially all the long-rangetesting of VX-478 that has to be done to bring the compound intoPhase I clinical trials."

Sato added, "We filed an IND [investigational new drug application]recently, and expect to start Phase I before the end of this quarter."

She made the point that "HIV protease inhibitors, VX-478especially, have potential to be used as stand-alone drugs, as well asin synergistic combination with retroviral transcription therapy, suchas AZT and ddi. Both opportunities are reflected in our clinical trialsdesign." n

-- David N. Leff Science Editor

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