Influenza virus A and B sialidase

Fig. 19. Inhibition of influenza virus A and B sialidases by cyclohexene-based amides 158 and 159. Numbers given in parentheses are IC50 values for NA(A) and NA(B), respectively. The IC50 values obtained for 1 under the same conditions were 0.005 pM for NA(A) and 0.004 pM for NA(B).

Another class of potent and selective influenza virus sialidase inhibitors which are orally active against influenza A and B, based on a cyclopentane framework, have also been described [54], Although not yet commercially available, BCX-1812 (RWJ-270201,5) has been subjected to Phase III clinical trials. BCX-1812 (5) is a nanomolar inhibitor of both influenza virus A and B sialidase and inhibits growth of influenza virus in tissue culture [55] and has demonstrated efficacy in a mouse influenza model... 

Because of the essential role of sialidase in influenza virus replication and the highly conserved enzyme active-site in influenza viruses A and B, most interest has been focused on the development of selective inhibitors of this enzyme.10 This chapter discusses the tremendous progress that has been made in the discovery of this new class of anti-influenza agents, in addition to some background information to understand the fundamental role of influenza. 

The differential inhibitory effect of the carboxamides on the sialidases from the influenza virus A and B was determined by extensive structure-activity... 

The most studied sialidase is the influenza virus neuraminidase, whose structure was reported over 15 years ago [9], and which has been the target of highly successful rational drug design [10-12]. Influenza type A and B viruses have two surface proteins, hemagglutinin (HA) which attaches the virus to host cells by recognizing sialic... 

Taylor NR, Cleasby A, Singh O, Skarzynski T, Wonacott AJ, Smith PW, Sollis SL, Howes PD, Cherry PC, Bethel R, Colman P, Varghese J (1998) Dihydropyrancarboxamides related to zanamivir a new series of inhibitors of influenza virus sialidases. Crystallographic and molecular modeling study of complexes of 4-amino-4//-pyran-6-carboxamides and sialidase from influenza virus types A and B. J Med Chem 41 798-807... 

The majority of other modifications examined at the C-4 position of Neu5Ac2en involved A -alkylation or /V-acylation of 4-amino-4-deoxy-Neu5Ac-2en or modification of the guanidino substituent of Zanamivir. IV-Methylamino (22), A -al lyl (23), and Ar,Ar-dimethylamino (24) derivatives of amine 9 were effective inhibitors of NA from influenza A and B viruses (A) = 10 5-10 7M) though they showed diminished activity against a number of bacterial sialidases.57,65... 

Interest in modification of the C-5 substituent of Neu5Ac2en arose in the 1960s when a group of eighteen ALacyl-modified Neu5Ac2en derivatives were screened against influenza A and B virus sialidases.58 Among these compounds, trifluoro-acetamide 37 and difluoroacetamide 38 were identified as the first inhibitors of... 

Removal of the C-8 and C-9 hydroxy groups in order to produce a hydro-phobic side-chain, gave such derivatives as 67, which were evaluated against influenza A and B virus sialidases and used in a viral-replication assay.82 While these molecules displayed similar efficacy to the parent triol against influenza A virus sialidase, they were relatively ineffective against influenza B virus. 

The currently most widely used class of antiviral inhibitors, however, has been developed by targeting the influenza virus sialidase, which is involved in the last stage of the life cycle of influenza A and B viruses [35], These inhibitors are discussed in detail in Section 17.7. 

X-ray crystal structure studies of influenza A/N2, A/N9, and B sialidases bound with a-Neu5Ac [66] show that the active site contains 18 invariant amino acid residues that either interact with the bound a-Neu5Ac or support these residues. These residues are conserved in all strains of influenza A and B viruses, suggesting their involvement in the enzymatic activity [65,66], The residues helped define the topology of the active site [66, 67], Of those conserved amino acids interacting with the substrate, many are polar, but there are also a number of nonpolar residues... 

A number of researchers have reported and demonstrated that maintaining the appropriate position of the substituents on a cyclic scaffold to interact with the established conserved amino acid residues involved in substrate binding can lead to development of new classes of influenza virus sialidase inhibitors [117]. Two drugs based on five-membered ring scaffolds have been developed as potent sialidase inhibitors. Cyclopentane derivative 24 (BCX-1812, peramivir) [117, 118] and pyrrolidine derivative 25 (ABT-675) [119] show nanomolar levels of inhibition of both influenza A and B viral sialidases (Fig. 17.13). 

A number of C-4-substituted 2,3-didehydro derivatives show significant inhibition of influenza A and B virus sialidase. The C-4 amino derivative (163) was originally targeted as a potential inhibitor of influenza virus sialidase based on molecular modelling studies of the X-ray crystal structure of influenza A virus sialidase [189-191]. 

Based on the lead compound BANA 113 42, which inhibits influenza A neuraminidase with a Ki of 2.5 p.M [91a,b], several novel 2-pyrrolidinone derivatives were designed. Whereas compound 43 (BANA 205) is a relatively weak inhibitor of influenza A and B neuraminidases, with IC50 values in the low micromolar range, compound 44 (BANA 206) is much more potent, with an IC50 value of 48 nM against influenza A neuraminidase. However, this compound is not as potent against influenza B virus sialidase [91d,e]. 

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