Neuraminidase inhibitors 4-

Clinical use of these drugs is limited not just because of their ineffectiveness against influenza B viruses, but also because of the rapid emergence of resistance [40]. A new class of agents, the neuraminidase inhibitors, has recently been developed that possesses significant activity against both influenza A and B strains. [Pg.821]

FIGURE 16.9 The antiviral adamantane amines amantadine 22 and rimantadine 23. [Pg.821]

Enzyme catalysis proceeds in four steps. The first step is the binding of the sialoside to the neuraminidase, which causes a considerable distortion of the Neu5Ac pyranose ring from a chair conformation to pseudoboat conformation. The second step leads to the formation of the endocyclic sialosyl cation transition-state via proton transfer from the solvent to the substrate. The final two steps are the formation and release of Neu5Ac [74c]. [Pg.822]

SCHEME 16.4 Proposed mechanism of catalysis of influenza virus neuraminidase [74c]. [Pg.823]

Compound 28, named zanamivir, was selected for clinical studies for the prophylaxis and treatment of influenza virus. Zanamivir was found to be suitable as a drug because it is highly selective for influenza type A and B viruses, which it inhibits with high potency [Pg.823]

The Diels-Alder reaction of nitroalkenes with Danishefsky s dienes is applied to synthesis of truncated carbocyclic analogues of a potent neuraminidase inhibitor 4-guanidino-NemAc en fsee Scheme 8.5. Carbocyclic analogs are found to retain interesting levels of antiviral activity comparable to those shovm by their oxygen-containing compounds in Scheme 8.5. [Pg.236]

Neuraminidase inhibitors are the major class of drugs to treat or to prevent the infection with influenza viruses. Currently, two neuraminidase inhibitors are available, zanamivir and oseltamivir, which block the release of new influenza vims from infected host cells and thereby stop the spread of infection. The enzyme neuraminidase is a surface glycoprotein present on all influenza viruses. There are nine influenza neuraminidase sub-types known of which subtypes N1 and N2 appear to be the most important ones. Neuraminidase inhibitors are effective against all neuraminidase subtypes. The activity of the neuraminidase is required for the newly... [Pg.821]

Alymova IV, Taylor G, and Portner A (2005). Neuraminidase inhibitors as antiviral agents. Current... [Pg.21]

Abed Y, Nehmd B, Baz M, Boivin G (2008) Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res 77 163-166... [Pg.145]

B neuraminidase and its complex with sialic acid. Embo J 11 49-56 Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RW (1993) Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1 19-26 Calfee DP, Hayden FG (1998) New approaches to influenza chemotherapy neuraminidase inhibitors, Drugs 56 537-553... [Pg.146]

Gubareva LV (2004) Molecular mechanisms of influenza virus resistance to neuraminidase inhibitors, Virus Res 103 199-203... [Pg.148]

Hagiwara T, Kijima-Suda I, Ido T, Ohrui H, Tomita K (1994) Inhibition of bacterial and viral sialidases by 3-fluoro-V-acetyIneuraminic acid, Carbohydr Res 263 167-172 Haskell TH, Peterson FE, Watson D, Plessas NR, Culbertson T (1970) Neuraminidase inhibition and viral chemotherapy, J Med Chem 13 697-704 Hatakeyama S, Sugaya N, Ito M, Yamazaki M, Ichikawa M, Kimura K, Kiso M, Shimizu H, Kawakami C, Koike K, Mitamura K, Kawaoka Y (2007) Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors, JAMA 297 1435-1442 Hay AJ (1992) The action of adamantanamines against influenza A viruses inhibition of the M2 ion channel protein, Semin Virol 3 21-30... [Pg.148]

Hurt AC, lanneUo P, Jachno K, Komadina N, Hampson AW, Barr IG, McKimm-Breschkin JL (2006) Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient, Antimicrob Agents Chemother 50 1872-1874 Hurt AC, Selleck P, Komadina N, Shaw R, Brown L, Barr IG (2007) Susceptibility of highly pathogenic A(H5N1) avian influenza viruses to the neuraminidase inhibitors and adamantanes. Antiviral Res 73 228-231... [Pg.148]

Kim CU, Lew W, Wilhams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG, Stevens RC (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119 681-690... [Pg.149]

Kim CU, Lew W, Wilhams MA, Wu H, Zhang L, Chen X, Escarpe PA, Mendel DB, Laver WG, Stevens RC (1998) Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors, J Med Chem 41 2451-2460 Kim CU, Chen X, Mendel DB (1999) Neuraminidase inhibitors as anti-influenza virus agents. Antiviral Chem Chemother 10 141-154... [Pg.149]

McKimm-Breschkin JL (2000) Resistance of influenza viruses to neuraminidase inhibitors - a review. Antiviral Res 47 1-17... [Pg.150]

Mishin VP, Hayden FG, Gubareva LV (2005) SusceptibUities of antiviral-resistant influenza viruses to novel neuraminidase inhibitors. Antimicrob Agents Chemother 49 4515 520 Molla A, Kati W, Carrick R, Steffy K, Shi Y, Montgomery D, Gusick N, Stoll VS, Stewart KD, Ng TI, Maring C, Kempf DJ, Kohlbrenner W (2002) In vitro selection and characterization of influenza A. (A/N9) virus variants resistant to a novel neuraminidase inhibitor, A-315675. J Virol 76 5380-5386... [Pg.150]

Sheu TG, Deyde VM, Okomo-Adhiambo M, Garten RJ, Xu X, Bright RA, Butler EN, Wallis TR, Klimov AI, Gubareva LV (2008) Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide from 2004 to 2008, Antimicrob Agents Chemother 52 3284-3292,... [Pg.151]

Smee DE, Huffman JH, Morrison AC, Barnard DL, Sidwell RW (2001) Cyclopentane neuraminidase inhibitors with potent in vitro anti-influenza virus activities. Antimicrob Agents Chemother 45 743-748... [Pg.152]

Smee DE, Bailey KW, Morrison AC, SidweU RW (2002) Combination treatment of influenza A virus infections in ceU culture and in mice with the cyclopentane neuraminidase inhibitor RWJ-270201 and ribavirin. Chemotherapy 48 88-93... [Pg.152]

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... [Pg.152]

Yen H-L, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, Govorkova EA (2005) Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother 49 4075 084 Zambon M, Hayden EG (2001) Position statement global neuraminidase inhibitor susceptibility network. Antiviral Res 49 147-156... [Pg.154]

Two neuraminidase inhibitors (oseltamivir carboxylate and zanamivir) are approved for prevention and treatment of infections with both influenza A and B viruses as discussed in chapter by Itzstein and Thomson, this volume. Oseltamivir carboxylate (OC) has gained most use because it can be taken orally, whereas the current formulation of zanamivir has to be inhaled. In addition, the WHO reconunends oseltamivir for treatment of clinically confirmed cases of H5N1 and for post-exposme prophylaxis to control recent H5N1 avian influenza outbreaks. [Pg.312]

Abed Y, Baz M, Boivin G (2006) Impact of neuraminidase mutations conferring influenza resistance to neuraminidase inhibitors in the N1 and N2 genetic backgrounds, Antivir Ther 11 971-976... [Pg.315]

Tai CY, Escarpe PA, Sidwell RW, WiUiams MA, Lew W, Wu H, Kim CU, Mendel DB (1998) Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071, Antimicrob Agents Chemother 42 3234-3241 Thomson MM, Najera R (2005) Molecular epidemiology of HlV-1 variants in the global AIDS pandemic an update. AIDS Rev 7 210-224... [Pg.320]

A-Acetyl-9-deoxy-9-fluoroneuraminic acid (591) was prepared by treatment of a protected 6-hydroxyl precursor with A, A-diethylaminosulfur trifluoride (DAST) or through condensation of 2-acetamido-2,6-dideoxy-6-fluoro-D-mannopyranose with potassium di(/ >r/-butyl) oxaloacetate. Compound 591 is a substrate for cytidine monophosphate (CMP)-sialic acid synthetase, giving rise to CMP-5-A-acetyl-9-deoxy-9-fluoroneuraminic acid, which is cytotoxic against tumor cells. 5-A-Acetyl-3-fluoroneuraminic acids 592-594 were prepared through fluorine (or acetyl hypofluorite) addition (in AcOH) to methyl 5-acetamido-4,7,8,9-tetra-0-acetyI-2,6-anhy-dro-2,3,5-trideoxy-D- /ycm>D- a/arto-non-2-enopyranosate. Compound 592 was found to be a potent neuraminidase inhibitor. [Pg.210]

Kim CU, Chen X, Mendel DB. Neuraminidase inhibitors as anti-influenza virus agents. Antiviral Chem Chemother 1999 10 141-154. [Pg.29]

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