Novel inhibitors of influenza sialidases related to GG167 structure-activity, crystallographic and Molecular dynamics studies with 4H-pyran-2-carboxylic acid 6-carboxamides

Smith, Paul W.; Sollis, Steven L.; Howes, Peter D.; Cherry, P. C.; Cobley, Kevin N.; Taylor, Helen V.; Whittington, Andrew R.; Scicinski, Jan; Bethell, Richard C.; Taylor, Nancy; Skarżyński, T.; Cleasby, Anne; Singh, Oncar; Wonacott, A.; Varghese, J.N.; Colman, Peter M.

doi:10.1016/s0960-894x(96)00542-2

Cited by 59 publications

(66 citation statements)

References 6 publications

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“…These results are consistent with previous reports that compounds which induce the Glu 278 side chain conformational change in Astrain enzymes are often 10-to 1,000-fold weaker inhibitors of B-strain neuraminidases (13,22,23). Although the active-site residues are strictly conserved between A and B strains of neuraminidase, the positions of the ␣-carbons and side chains do not overlie exactly in three dimensions.…”

supporting

confidence: 92%

“…Although the active-site residues are strictly conserved between A and B strains of neuraminidase, the positions of the ␣-carbons and side chains do not overlie exactly in three dimensions. Whereas the Glu 278 conformational change can occur quite easily in the Astrain enzyme in order to accommodate a ligand, a similar conformational change in the B-strain Glu 278 results in unfavorable steric interactions and a distortion of the protein backbone (22). The net result is that the Glu 278 conformational change is less energetically favorable in B-strain neuraminidase, accounting for the binding affinity differences between A-and B-strain enzymes.…”

mentioning

confidence: 99%

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Novel α- and β-Amino Acid Inhibitors of Influenza Virus Neuraminidase

Kati

Montgomery

Maring

et al. 2001

Antimicrob Agents Chemother

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In an effort to discover novel, noncarbohydrate inhibitors of influenza virus neuraminidase we hypothesized that compounds which contain positively charged amino groups in an appropriate position to interact with the Asp 152 or Tyr 406 side chains might be bound tightly by the enzyme. Testing of 300 ␣-and ␤-amino acids led to the discovery of two novel neuraminidase inhibitors, a phenylglycine and a pyrrolidine, which exhibited K i values in the 50 M range versus influenza virus A/N2/Tokyo/3/67 neuraminidase but which exhibited weaker activity against influenza virus B/Memphis/3/89 neuraminidase. Limited optimization of the pyrrolidine series resulted in a compound which was about 24-fold more potent than 2-deoxy-2,3-dehydro-N-acetylneuraminic acid in an anti-influenza cell culture assay using A/N2/Victoria/3/75 virus. X-ray structural studies of A/N9 neuraminidase-inhibitor complexes revealed that both classes of inhibitors induced the Glu 278 side chain to undergo a small conformational change, but these compounds did not show time-dependent inhibition. Crystallography also established that the ␣-amino group of the phenylglycine formed hydrogen bonds to the Asp 152 carboxylate as expected. Likewise, the ␤-amino group of the pyrrolidine forms an interaction with the Tyr 406 hydroxyl group and represents the first compound known to make an interaction with this absolutely conserved residue. Phenylglycine and pyrrolidine analogs in which the ␣-or ␤-amino groups were replaced with hydroxyl groups were 365-and 2,600-fold weaker inhibitors, respectively. These results underscore the importance of the amino group interactions with the Asp 152 and Tyr 406 side chains and have implications for anti-influenza drug design.The catalytic power of enzymes arises from their ability to bind the altered substrate in the transition state much more tightly than the substrate in its unaltered, ground state form (28,29). The magnitude of this binding affinity discrimination can be estimated from a comparison of the rate constants for the enzymatic and nonenzymatic reactions (29) and appears to range between 10 8 -and 10 17 -fold for most enzymes (7, 30). Any stable compound whose chemical structure resembles that of the transition state should capture some fraction of this binding affinity advantage, resulting in a potent and specific inhibitor of the target enzyme. Compounds believed to mimic the structure of the transition state or of an intermediate in the reaction pathway have been described for well over 100 different enzymes (29, 31).Influenza neuraminidase is one enzyme for which a putative transition state analog has been described (10). This enzyme is present on the viral surface and functions to cleave terminal ␣-ketosidically linked N-acetylneuraminic acid residues from glycoproteins, glycolipids, and oligosaccharides in a reaction which is essential for effective replication of the influenza virus (20). Enzyme kinetic isotope effect studies (5) have established that the neuraminidase hydrolytic reaction proceeds throug...

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confidence: 92%

mentioning

confidence: 99%

Novel α- and β-Amino Acid Inhibitors of Influenza Virus Neuraminidase

Kati

Montgomery

Maring

et al. 2001

Antimicrob Agents Chemother

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“…Toward this goal, in two recent communications we disclosed a preliminary account of a new series of 4H-pyrancarboxamide influenza sialidase inhibitors derived from zanamivir. 28,29 More recently workers from Gilead have claimed GS4104 (the ethyl ester prodrug of GS4071) to be an orally active influenza sialidase inhibitor in mouse models of efficacy. 30, 31 Herein we describe further details of our discovery of the carboxamide inhibitors (of general formulas 4 and 5) and disclose further SAR.…”

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confidence: 99%

Dihydropyrancarboxamides Related to Zanamivir: A New Series of Inhibitors of Influenza Virus Sialidases. 1. Discovery, Synthesis, Biological Activity, and Structure−Activity Relationships of 4-Guanidino- and 4-Amino-4H-pyran-6-carboxamides

et al. 1998

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4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.

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“…The x-ray structure of influenza virus NA has been determined (8,9) for type A subtype N2 (10), N9 (11,12), and type B (13), together with their complexes with Neu5Ac (14) and other NA inhibitors (15)(16)(17). These structural studies have led to a renewed interest in NA inhibitors as a means of controlling influenza virus infections.…”

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confidence: 99%

Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases

Varghese¹,

Colman²,

Donkelaar³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

118

151

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The x-ray structure of a complex of sialic acid (Neu5Ac) with neuraminidase N9 subtype from A͞tern͞ Australia͞G70C͞75 inf luenza virus at 4°C has revealed the location of a second Neu5Ac binding site on the surface of the enzyme. At 18°C, only the enzyme active site contains bound Neu5Ac. Neu5Ac binds in the second site in the chair conformation in a similar way to which it binds to hemagglutinin. The residues that interact with Neu5Ac at this second site are mostly conserved in avian strains, but not in human and swine strains, indicating that it has some as-yet-unknown biological function in birds.

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Novel inhibitors of influenza sialidases related to GG167 structure-activity, crystallographic and Molecular dynamics studies with 4H-pyran-2-carboxylic acid 6-carboxamides

Cited by 59 publications

References 6 publications

Novel α- and β-Amino Acid Inhibitors of Influenza Virus Neuraminidase

Novel α- and β-Amino Acid Inhibitors of Influenza Virus Neuraminidase

Dihydropyrancarboxamides Related to Zanamivir: A New Series of Inhibitors of Influenza Virus Sialidases. 1. Discovery, Synthesis, Biological Activity, and Structure−Activity Relationships of 4-Guanidino- and 4-Amino-4H-pyran-6-carboxamides

Structural evidence for a second sialic acid binding site in avian influenza virus neuraminidases

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