The HCV Combo Race Just Got Hotter
Jan13

The HCV Combo Race Just Got Hotter

BMS is shelling out $2.5 billion dollars for Inhibitex, a small pharma company with a Phase II molecule for treatment of Hepatitis C (HCV). The deal adds to the scramble for HCV assets in recent months, with Gilead agreeing to pay almost $11 billion for Pharmasset in November, and Roche’s recent purchase of Anadys. While much has been written about the merits (and price tags) of each deal, the Haystack thought it was worth taking a closer look at the chemical composition of the multi-million dollar molecules. So what did BMS get for their money? INX-089, Inhibitex’s lead molecule, has a common antiviral motif: a nucleoside core (the 5-membered ring sugar attached to a nitrogen heterocycle) with an amino acid based prodrug hanging off the left-hand side. Clinically-tested antivirals sharing this basic setup include IDX-184 and NM-283, both from Idenix, and PSI-352938, from Pharmasset  (For an overview of the varied structures currently in development for HCV, see Lisa’s 2010 C&EN story). INX-089 bears a close resemblance to Pharmasset’s lead nucleotide inhibitor PSI-7977. That’s not a mistake, believes ‘089 discoverer Chris McGuigan, of the Welsh School of Pharmacy. In a recent article (J. Med. Chem. 2010, 53, 4949), McGuigan himself comments “The Pharmasset nucleoside [is] rather parallel to our early work on anti-HIV ProTides.” Wait, what are ProTides? Both INX-089 and PSI-7977 aren’t themselves the active viral inhibitor, but phosphoramidate “ProTide” prodrugs: compounds broken down by the body into the active drug (Chem Note: PSI-7977 has single-enantiomer Sp chirality at phosphorus, while INX-189 is a mixture of diastereomers). Once in the body, enzymes cleave the phosphoramidate group to a phosphate (PO42-). Kinases attach two more phosphate groups, and viruses let this dressed-up molecule inside, where the nucleotide warhead inhibits HCV by interfering with RNA replication (Antimicrob. Agents Chemother. 2011, 55, 1843). A few comments on the drug itself: The similarity of the ProTide portion (left-hand side) of the molecule to PSI-7977 really is striking: swap in an isobutyl ester and a phenyl, and it’s the same beast! The more interesting switch comes on the upper-right (“eastern”) part of the structure: a protected guanosine ring. This ring harks back to guanine, one of the four common nucleic acids found in DNA. PSI-7977, meanwhile, shows off a uracil, a nucleic acid found in RNA, not DNA. Although it’s tempting to think such similar compounds all dock into the NS5B polymerase at the active site (in the yellow “palm” of the hand-shaped enzyme), don’t be too sure – a recent paper by Pharmasset scientists (J. Med. Chem. 2012, Just Accepted) shows quite a few “Finger,” “Palm,” and “Thumb” sites.  It’s not yet clear whether...

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Hey, ACS, Where’s My Coloring Book?
Jan06

Hey, ACS, Where’s My Coloring Book?

There was nothing I liked to do better when I was a young lass than to put crayons to the pages of my coloring books. Staying inside the lines was decidedly cool, and anyone who couldn’t manage it wasn’t allowed to defile my beloved “Sleeping Beauty” or “Aladdin” books. Even today, I have a soft spot for coloring books, so when I see one as fantastic as Cell Press’s “Coloring With Cell,” I think it deserves a mention. I picked up this fun book at a Cell symposium late last year; it came with the registration materials. Immediately, I was in love with the book, made especially for young and old geeks everywhere. Inside, Sammy The Cell guides you through the pages, describing the parts inside cells, how membrane channels work, and into what forms stem cells can differentiate. A particular favorite is the connect-the-dots activity you can do to reveal RNA polymerase stuck to some DNA. This rad coloring book got me to thinking: “What would an American Chemical Society coloring book look like? What sorts of things would it ask tiny chemists to color?” Some flasks and beakers of course, and some ball-and-stick molecules to be sure. Perhaps the periodic table, a bit of safety gear, and our dear mascot, Milli Mole. But what else? Newscripts readers: What would you want to see in a coloring book geared toward getting people excited about chemistry? (And ACS, when are you going to print one, please?) Is it easier or harder to come up with things to color than for biology? I recently shared “Coloring With Cell” with my 10-year-old niece, who wasn’t quite sure at first what to make of the book but humored me by coloring a page or two. In the end, though, she asked if I could bring it back so she could finish coloring a virus particle. Sweeter words I’ve never heard. Other Newscripts coloring book reading: “Backyard Gas, Crafty Chemistry,” where kids learn about the wonders of...

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