Carbocycles Related to Oseltamivir as Influenza Virus Group-1-Specific Neuraminidase Inhibitors. Binding to N1 Enzymes in the Context of Virus-like Particles

Abstract

We report here the exploitation of the 150-cavity in the active sites of group-1 neuraminidases for the design of new triazole-containing carbocycles related to oseltamivir. Inhibition studies with virus-like particles (VLPs) containing the influenza virus neuraminidase-1 (N1) activity indicate that several candidates are inhibitors, with K(i) values in the 10(-5)-10(-8) M range. In contrast, a known candidate that preserves the free amino group and a new candidate containing a guanidine function are better inhibitors, with K(i) values of 1.5 × 10(-9) and 4.6 × 10(-10) M, respectively. The most active inhibitor of the N1 enzyme in the triazole series was selective for the N1 class and showed significantly less inhibition (K(i) = 2.6 μM vs 0.07 μM) of the free influenza virus neuraminidase-2 (N2). In addition, saturation transfer difference (STD) NMR spectroscopic studies with this compound and the VLPs show that the entire molecule forms contacts with residues in the active site. These data taken together support our proposed binding mode in which the active site and the adjoining 150-cavity are both occupied.

Structural and functional characterization of neuraminidase-like molecule N10 derived from bat influenza A virus

“…Extensive structural and functional studies of group 2 influenza NAs have led to the development of NA as the most successful drug target against flu to date (10-16). The recent identification of group 1 NA structures, including H5N1 NA (17), pandemic 2009 H1N1 NA (09N1) (18), 1918 H1N1 NA (18N1) (19), N4 (17), N5 (20), and N8 (17), further illustrates the complexity of influenza NA structures and offers some ideas for the design of next-generation NA inhibitors (21,22). However, the identification of N10 revealed an NA-like protein that is significantly divergent from other influenza NAs (7), and thus whether N10 has special structural and/or functional features remains unknown.…”

Resistance to Mutant Group 2 Influenza Virus Neuraminidases of an Oseltamivir-Zanamivir Hybrid Inhibitor

“…Analysis of the crystal structures of the N2 I222L and E119V mutants and the N2-I222L/E119V dual mutant reveals that a loss of a salt bridge due to the E119V substitution and a change in the hydrophobic environment due to the I222L substitution likely confer multidrug resistance. However, we found that this drug resistance can be overcome by a novel hybrid inhibitor, MS-257, which has both the guanidino group of zanamivir and hydrophobic pentyloxy group of oseltamivir (36,37). Previously, our group has reported the reduced susceptibility of MS-257 to a known oseltamivir resistance mutation, H274Y (H1N1) (38).…”

Selective functionalization of alicyclic beta-amino acids by 1,3-dipolar cycloaddition of nitrile oxides

“…As a consequence of their ability to undergo reductive ring opening, isoxazolines are of interest as precursors for the synthesis of highly functionalized molecules such as β-hydroxyketones [7][8][9][10], amino alcohols or amino acids [11][12][13][14][15][16][17], etc. The multifunctionalized cyclic amino acids -e.g., the antibiotic Oryzoxymycin [18][19][20][21], the antiviral agents Tamiflu [22][23][24][25][26][27][28][29][30][31][32][33], Zanamivir and 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA) [34][35][36][37][38] -are bioactive derivatives of great significance for medicinal chemistry. A promising neuraminidase inhibitor, BCX-1812 (Peramivir), is currently under evaluation in clinical trials [39][40][41][42][43][44][45] (Figure 1).…”