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Document Figure 7 Stereo image of the active site of Tern/N9 showing the active-site residues surrounding 4-guanidino-Neu5Ac2en (black). Those residues that are conserved in both influenza and bacterial neuraminidase are shaded gray, and those that are conserved only in influenza virus neuraminidase are not shaded. sufficient sialic acid at the cell surface to enable attachment via the hemagglutinin. This balance may require some configuration of residues in the active site not directly responsible for catalysis but only involved in the binding and release of sialic acid. IV. Neuraminidase Inhibitor Design Page 472 Earlier screening programs [73] failed to identify potent inhibitors of viral neuraminidase. The first inhibitor synthesized [74] with a K i value in the micromolar range was Neu5Ac2en. This was based on the proposed transition state of the reaction, where the anomeric carbon (C2) bound to the ketosidic oxygen has a trigonal state. Several analogues of Neu5Ac2en were synthesized soon after, and the most potent of these, a trifluoracetyl derivative, had a K i of only 0.8 μM [75]. While this compound showed that in cell culture it retarded virus shedding [34,76], it failed as an effective antiviral agent in animals [77]. The x-ray structure of Neu5Ac2en/neuraminidase complexes have been determined for N2 [66], type B [78], and N9 [79]. The Neu5Ac2en molecule binds in the active site of neuraminidase with the carboxylate oxygen atoms placed in the same location as the carboxylate of sialic acid. The 5-N-acetyl, 4- http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_472.html [4/9/2004 12:22:48 AM]
Document hydroxy, and 6 Neu5Ac2en -glycerol are positioned isosterically in the two molecules. Page 473 An alternative approach to develop sialidase inhibitors has been made using synthetic thioglycoside analogs of gangliosides such as Neu5Aca(2-S-6)Glcb(1-1)Ceramide [80] were shown to inhibit different subtypes of human and animal influenza virus with K i values of up to 2.8 μM. These metabolically stable ganglioside analogs contain a thioglycosidic linkage to the terminal neuraminic acid that resists cleavage by the enzyme. Several flavonoid neuraminidase inhibitors have been isolated from plant extracts [81], one of which 5,7,4'-trihydroxy-8-methoxyflavone, was a more potent inhibitor than Neu5Ac2en. Recently, in vivo anti-influenza virus activity of a Kampo (Japanese herbal medicine) preparation has shown promising results in inhibiting influenza virus replication in mice [82], but the mode of action of these compounds is unclear. A. Enzyme Mechanism The similar positioning of the carboxylate oxygens and ring of Neu5Ac2en and sialic acid suggests that Neu5Ac2en is probably a transition state analog. As Neu5Ac2en has a higher affinity for neuraminidase than sialic acid, a mechanism of catalysis was proposed [83] that involves the distortion of the substrate by the formation of a oxycarbonium ion intermediate, which has a similar structure to Neu5Ac2en. However the structural results from sialic acid/neuraminidase complexes suggest that the tighter binding of Neu5Ac2en more likely comes from the relaxation of the conformational strain arising from the transition from chair to boat of the pyranose ring of sialic acid in the active site [66]. Evidence for a sialyl cation transition state by isotopic effects [84] support the existence of a oxycarbonium ion intermediate. However the structural basis for neuraminidase activity is still unclear. It has been suggested [66] that the tyrosyl oxygen of Tyr406, assisted by the sialic acid carboxylate itself, could stabilize the developing charge on the oxycarbonium ion intermediate. The reaction would be completed by the activation of a water molecule by a deprotonated Asp151 and its attack on the carbonium, resulting in the formation of the α-anomer of sialic acid [85]. However the pH-activity profile of neuraminidase [86,87,78] suggests a bell-shaped profile, which indicates normal activity from a pH range of about 4.5 to 9. This would indicate that the role of Asp151 as the acid group in the catalysis is unclear. A nonspecific proton donor has been proposed [78], probably a water molecule as the acid group, with a deprotonated Tyr406 stabilizing the oxycarbonium ion, and a proton transferred from water to the departing aglycon group. It has also been postulated that a proton is eliminated at C3 leading to the transformation http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_473.html [4/9/2004 12:23:02 AM]
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Structure-based Drug Design 14 Stru
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Document dine) and didanosine (dide
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Page 541 and 542: Document 17 Structure and Functiona
Page 543 and 544: Document Table 1 Approval Indicatio
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