NEWS OF THE WEEK
INHIBITORS MAY BE FLU DRUG BACKUPS
aminidase works molecularly (Science, DOI: 10.1126/ Neuraminidase’s science.1232552). Their study shows that neuraminidase native substrate, catalyzes sialic acid cleavage by a mechanism involving sialic acid (top), a covalent intermediate. They determined the structure is structurally similar to new of the intermediate and designed sialic acid analogs DRUG DISCOVERY: Agents block mechanismthat bond covalently to the viral neuraminidase active based flu enzyme virus by new mechanism that site but release very slowly, thus disabling it, and do not inhibitors (such could help prevent resistance inhibit human neuraminidase. The compounds may as the one shown, evade viral resistance more effectively than Tamiflu bebottom). cause their structures more closely resemble that OH OH O HE RISE OF INFLUENZA STRAINS resistant to of sialic acid. Also, covalent bonding permanently HO current flu treatments has drug developers look- inactivates the neuraminidase active site; Tamiflu H O O ing for new leads. Hope could come from a new and the three other inhibitors bind noncovalently. N O family of inhibitors that may effectively block the flu viThe Centre for Drug Research & Development, HO HO rus from spreading in the body and thwart its tendency in Vancouver, is seeking private-sector partners to become drug-resistant. and investors to help develop the new inhibitors The new agents, devised by a University of British commercially. OH OH O Columbia-based team, inhibit the flu virus enzyme Drug-resistant viruses that cause pandemics HO neuraminidase. They halt the spread of flu viruses in “could be devastating for lack of any means to limit H F O N cell culture and animal tests, including strains resistant their spread or pathology,” comments chemical F O HO HN to the commercial flu drug Tamiflu, which also inhibits glycobiologist James C. Paulson of Scripps ReNH neuraminidase. The compounds could therefore lead search Institute, in California. The new inhibitors H2N to a Tamiflu backup drug. “should be developed as drugs for human testing Flu afflicts millions worldwide each year, causing that could be stockpiled or serve as debilitating symptoms and hundreds of thousands of alternatives.” deaths. When the virus infects people, it enters airway Relenza discoverer Mark von cells and replicates. Progeny emerge as buds attached Itzstein of Griffith University, in to sialic acids on cell surfaces. If neuraminidase cleaves Australia, says the new data “prothese acids, the viruses are released to infect more cells. vide valuable insight into possible Inhibitors turn off this activity, blocking proliferation. next-generation influenza drugs.” Four neuraminidase inhibitors are approved or in deFlu expert Larisa V. Gubareva of velopment for postinfection treatment. Tamiflu is the the Centers for Disease Control & most popular, but flu can evolve into strains insensitive Prevention, in Atlanta, is more cauto it. Relenza is administered by oral inhalation, which tious, saying that discovery of the has limited its use. Peramivir was withdrawn from a covalent mechanism is noteworthy Phase III trial last year, and laninamivir is scheduled to but the new inhibitors’ efficacy and Virus (blue sphere) adheres to sialic enter Phase II, although both are approved in Asia. advantages over existing inhibitors acids (green) on host cell surface (red). The new compounds emerged from efforts by Stehave yet to be fully evaluated.—STU Inhibitors (yellow) block active site phen G. Withers and coworkers to determine how neur- BORMAN of neuraminidase (blue appendages), preventing the enzyme from cleaving VIDEO ONLINE See inhibitors trap flu virus progeny at http://cenm.ag/flu. sialic acid to let the virus spread. CSI RO
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FINE CHEMICALS Informex attendees are buoyed by return of business from Asia The fine and custom chemical executives gathered in Anaheim, Calif., last week for the annual Informex exhibition reported that business continues to be strong in pharmaceuticals. A shift in contract manufacturing from China and India back to the West has provided a steady boost to the sector, they said. Susan B. Billings, business development manager for Albany Molecular Research Inc., said drug and biotech companies are increasingly interested in working with contract research and manufacturing
firms with integrated drug discovery capabilities, “and they are willing to pay for it.” At the end of collaboration, Billings said, they want to have meaningful outcomes such as a clinical candidate that they can advance. AMRI has increased its medicinal chemistry resources in the U.S. by 50% since 2011, she said. Ampac Fine Chemicals is currently installing its third small-scale, high-tech manufacturing line, or semiworks, at its California site to accommodate an increased demand for unique chemistry
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at small volumes, noted President Aslam Malik. “We are seeing demand for more complex, potent, and chiral chemistry,” he said, “but the volume is going down.” Meanwhile, Asymchem, a U.S.-based firm that does all its manufacturing in China, has been investing in specialized flow chemistry and enzymatic manufacturing, according to Matt Johnson, director of chemical development. “We don’t want to be continually perceived as the cheap alternative to Western supply,” Johnson said.—RICK MULLIN
