Neuraminidase inhibitors neuraminic acid

Bossart-Whitaker P, Carson M, Babu YS, Smith CD, Laver WG, Air GM (1993) Three-dimensional structure of influenza A N9 neuraminidase and its complex with the inhibitor 2-deoxy 2,3-dehydro-V-acetyl neuraminic acid. J Mol Biol 232 1069-1083 Burmeister WP, Ruigrok RW, Cusack S (1992) The 2.2 A resolution crystal structure of influenza... 

A. Oseltamivir inhibits neuraminidase, an enzyme that cleaves neuraminic acid from oligosaccharides. Neuraminidase activity aids the movement of viral particles through neuraminic acid-rich respiratory secretions and is required for the release of progeny virions. Inhibition of viral DNA polymerase is the mechanism of action of nucleoside analogue antiviral drugs. Interferons do stimulate the JAK-STAT signaling pathway but do not stimulate proliferation of immune cells. Ribavirin inhibits GTP synthesis, and the antiretroviral protease inhibitors (e.g., ritonavir) inhibit HIV protease. 

The structures of TV-acetyl neuraminic acid (sialic acid Neu5Ac) and the 2-deoxy-2,3-dehydro-/V-acetyl neuraminic acid (Neu5Ac2en) inhibitor complexed with N2 neuraminidase [66] revealed the nature of the interactions of the... 

Neuraminidase inhibitors prevent the release of influenza A and B viruses. Normally, the viral neuraminidase splits off N-acetyl-neuraminic (sialic) acid residues on the cellular surface coat, thereby enabling newly formed viral particles to be detached from the host cell. Zanamivir is given by inhalation oseltamivir is suitable for oral administration because it is an ester prodrug. Possible uses include treatment and prophylaxis of influenza virus infections. 

Special interest has been taken in the inhibition of enzymes involved in cleaving the glycosidic bonds of neuraminic acid (a complex C9-carbon sugar acid), because this process is critical to the spread of infection after the influenza virus binds to the host cell. Following the analysis of the structure of complexes of the enzyme and substrate (bound in a distorted conformation), unsaturated compounds, for example 43 (Figure 1.14), were made as mimics of the latter in the reaction transition state and found to be potent neuraminidase inhibitors and anti-influenza compounds [49]. 

Vaccination can prevent the spread of flu, but influenza vaccines are slow to produce and difficult to generalize because of the rate of mutation of the virus. So the first line of defence is a class of antiviral compounds known as neuraminidase inhibitors. Neuraminidase is an enzyme used by the flu virus that targets human cell-surface carbohydrates containing neuraminic acids and allows the virus to release itself from the host cell. Inhibition of this enzyme prevents the new virus particles from spreading. 

A new 8-step synthesis of the neuraminidase inhibitor 19 from neuraminic acid has been outlined, and a number of analogues 18 with modified substituents on N-5, as well as a 6-thio-analogue, " have been prepared and evaluated as neuraminidase inhibitors. The carboxamides 20 and 21 have also been synthe-... 

Sialic acid was the first virus receptor identified. Hirst and McClelland and Hare discovered that influenza virus is able to hemagglutinate and that adsorbed virus is eluted from erythrocytes on incubation at 37°C, indicating an enzymatic destruction of a receptor substance on the cells [1, 2]. When a similar enzymatic activity was subsequently detected in Vibrio cholerae cultures, the term receptor-destroying enzyme was introduced [3]. The substance released by the viral enzyme from soluble hemagglutination inhibitors was initially characterized as a carbohydrate of low molecular weight [4] and then identified in crystalline form as A-acetyl-o-neuraminic acid [5]. Thus, it was clear that the receptor determinant of influenza virus was sialic acid and that the viral enzyme was a neuraminidase. Furthermore, for the first time an important biological function of sialic acid had been identified. 

Influenza vims A has two surface glycoproteins that offer potential for the development of competitive multivalent sugar clusters featuring 5-A -acetyl neuraminic acid (Neu5Ac) units [35]. Haemagglutinin (HA) binds to sialic acid receptors and fuses the cell membranes of the vims and host and neuraminidase (NA), an enzyme, cleaves sialic acid residues and is involved in release of new vims by the host cell. Whilst small molecule inhibitors of NA, such as oseltamivir (Tamiflu) and zanamavir (Relenza), are now available, no therapy based on inhibition of binding of HA has reached the clinic. 

A synthesis of the neuraminidase inhibitor 4-deoxy-4-guanidino-neuraminic acid derivative 28 from neuraminic acid has been effected and a number of N-substituted guanidines were also prepared,while further chain-shortened analogues of 28 have been prepared without C-9 then C-8 and then C-7. Other analogues 29 have been prepared from Kdn and the 5-deoxy-derivative 30 has been synthesized from 2-deoxy-D-arafewio-hexose by way of an aldolase-catalysed reaction with pyruvic acid. Neuraminic acid has also been converted into the 3,4-dideoxy-4-guanidino derivative 31. ... 

Privalova, I. M., and Khorlin, A. Ya., 1%9, Substrates and inhibitors of neuraminidases. Communication synthesis of 0-, 5-, and N-ketosides of N-acetyl-o-neuraminic acid, Izv. Akad. Nauk SSSR, Ser. Khim. 1969 2785 (Eng. trans. p. 2614). 

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