A Study of the Active Site of Influenza Virus Sialidase:  An Approach to the Rational Design of Novel Anti-influenza Drugs

Itzstein, Mark von; Dyason, Jeffrey Clifford; Oliver, Stuart W.; White, Hume F.; Wu, Wen-Yang; Kok, Gaik B.; Pegg, Michael S.

doi:10.1021/jm950294c

Cited by 113 publications

(77 citation statements)

References 17 publications

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“…Once the structure of the TS is known for reactions with a single barrier, the GRID potential, in combination with automated procedures, [44] can be used for a fast screening of large databases in search of better TSAs. This approach has been proven to be successful in drug design [45] by focusing on the molecular recognition between enzymes and their substrates. A further refinement step, on the first set of candidates selected in this way, may be introduced for the design of haptens that will elicit optimal CAs.…”

Section: Discussionmentioning

confidence: 99%

On the Generation of Catalytic Antibodies by Transition State Analogues

Barbany¹,

Gutiérrez‐de‐Terán²,

Sanz³

et al. 2003

ChemBioChem

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The effective design of catalytic antibodies represents a major conceptual and practical challenge. It is implicitly assumed that a proper transition state analogue (TSA) can elicit a catalytic antibody (CA) that will catalyze the given reaction in a similar way to an enzyme that would evolve (or was evolved) to catalyze this reaction. However, in most cases it was found that the TSA used produced CAs with relatively low rate enhancement as compared to the corresponding enzymes, when these exist. The present work explores the origin of this problem, by developing two approaches that examine the similarity of the TSA and the corresponding transition state (TS). These analyses are used to assess the proficiency of the CA generated by the given TSA. Both approaches focus on electrostatic effects that have been found to play a major role in enzymatic reactions. The first method uses molecular interaction potentials to look for the similarity between the TSA and the TS and, in principle, to help in designing new haptens by using 3D quantitative structure-activity relationships. The second and more quantitative approach generates a grid of Langevin dipoles, which are polarized by the TSA, and then uses the grid to bind the TS. Comparison of the resulting binding energy with the binding energy of the TS to the grid that was polarized by the TS provides an estimate of the proficiency of the given CA. Our methods are used in examining the origin of the difference between the catalytic power of the 1F7 CA and chorismate mutase. It is demonstrated that the relatively small changes in charge and structure between the TS and TSA are sufficient to account for the difference in proficiency between the CA and the enzyme. Apparently the environment that was preorganized to stabilize the TSA charge distribution does not provide a sufficient stabilization to the TS. The general implications of our findings and the difficulties in designing a perfect TSA are discussed. Finally, the possible use of our approach in screening for an optimal TSA is pointed out.

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Section: Discussionmentioning

confidence: 99%

On the Generation of Catalytic Antibodies by Transition State Analogues

Barbany¹,

Gutiérrez‐de‐Terán²,

Sanz³

et al. 2003

ChemBioChem

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“…Several potent and selective inhibitors, e.g., oseltamivir carboxylate (Ro64-0802, GS4071) and zanamivir (Relenza, GG167), of the influenza NA have been discovered through structure-based rational drug design (19,21,46). Oseltamivir carboxylate, the active metabolite of oseltamivir phosphate (Tamiflu, Ro64-0796, GS4104), is a potent and specific inhibitor of influenza A and B virus NA (26,27,48).…”

mentioning

confidence: 99%

Mechanism by Which Mutations at His274 Alter Sensitivity of Influenza A Virus N1 Neuraminidase to Oseltamivir Carboxylate and Zanamivir

Wang

Tai

Mendel

2002

Antimicrob Agents Chemother

147

115

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Oseltamivir carboxylate is a potent and specific inhibitor of influenza neuraminidase (NA). An influenza A/H1N1 variant selected in vitro with reduced susceptibility to oseltamivir carboxylate contains a His274Tyr mutation. To understand the mechanism by which a His274Tyr mutation gives rise to drug resistance, we studied a series of NA variant proteins containing various substitutions at position 274. Replacement of His274 with larger side chain residues (Tyr or Phe) reduced the NA sensitivity to oseltamivir carboxylate. In contrast, replacement of His274 with smaller side chain residues (Gly, Asn, Ser, and Gln) resulted in enhanced or unchanged sensitivity to oseltamivir carboxylate. Previous studies have suggested that the slow-binding inhibition of NA by oseltamivir carboxylate is a result of the reorientation of Glu276. Loss of this slow-binding inhibition in the His274Tyr and His274Phe mutant NA but not in His274Asn, His274Gly, His274Ser, or His274Gln supports the conclusion that the conformational change of Glu276 is restricted in the His274Tyr and His274Phe mutant NA upon oseltamivir carboxylate binding. Interestingly, His274Asn, as well as His274Gly, His274Ser, and His274Gln, also displayed reduced sensitivity to zanamivir and its analogue, 4-amino-Neu5Ac2en. Substitution of His274 with Tyr in influenza A/Tokyo/3/67 (H3N2) recombinant NA did not affect the susceptibility to oseltamivir carboxylate. These data indicate that the volume occupied by the amino acid side chain at position 274 can influence the sensitivities of influenza N1 NA but not of N2 NA to both oseltamivir carboxylate and zanamivir.

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“…[5][6][7] A new class of antivirals, with a different mechanism of antiviral action, has been designed and developed to provide another approach to the control of influenza. 8,9 The compounds specifically inhibit the action of the viral neuraminidase enzyme, essential for replication of both type A and B viruses. The sites affected are conserved; thus, the antiviral action is independent of antigenic change.…”

mentioning

confidence: 99%

“…The sites affected are conserved; thus, the antiviral action is independent of antigenic change. 8,9 Zanamivir (GG167), a sialic acid analog, has been demonstrated to be efficacious in clinical trials in shortening the duration and reducing the severity of type A and B influenza illness. 10 Ex-perimental studies have suggested promise in the prevention of influenza.…”

mentioning

confidence: 99%