title: The de-guanidinylated derivative of peramivir remains a potent inhibitor of influenza neuraminidase.
abstract: The guanidine function in the potent neuraminidase inhibitor peramivir was included early on in the drug design process, and examination of X-ray structural data for the enzyme-inhibitor complex would seem to indicate that the guanidine plays a critical role in promoting binding. However, this functional group may also contribute to the poor oral availability of the drug. Given that the relative stereochemistry on the guanidine-bearing carbon in peramivir is opposite to that in zanamivir (a related neuraminidase inhibitor, for which the guanidine function is known to contribute substantially to the potency), we sought to determine the importance of the guanidine group to peramivir's overall potency. Here we report that the de-guanidinylated analogue of peramivir is only ca. 1-order of magnitude less potent than peramivir itself in two in vitro inhibition assays. This suggests that next-generation inhibitors designed to improve on peramivir's properties might profitably dispense with the guanidine function.
authors: Department of Chemistry, University of Victoria, Victoria, BC, Canada.
authors: Caleb M
authors: CM
authors: Bromba
authors: Jeremy W
authors: JW
authors: Mason
authors: Michael G
authors: MG
authors: Brant
authors: Tracy
authors: T
authors: Chan
authors: Martine D
authors: MD
authors: Lunke
authors: Martin
authors: M
authors: Petric
authors: Martin J
authors: MJ
authors: Boulanger
authors: Jeremy E
authors: JE
authors: Wulff
mesh_terms: D000146:Acids, Carbocyclic; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D011485:Protein Binding; D011994:Recombinant Proteins / Q000235:genetics; D053243:Zanamivir / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D011994:Recombinant Proteins; D009439:Neuraminidase; D053243:Zanamivir; C414210:peramivir