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. 2010 Nov 16:1:113.
doi: 10.1038/ncomms1114.

Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

Santosh Rudrawar  1 , Jeffrey C Dyason, Marie-Anne Rameix-Welti, Faith J Rose, Philip S Kerry, Rupert J M Russell, Sylvie van der Werf, Robin J Thomson, Nadia Naffakh, Mark von Itzstein
Affiliations
Free PMC article

Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase

Santosh Rudrawar et al. Nat Commun. .
Free PMC article

Abstract

Influenza virus sialidase has an essential role in the virus' life cycle. Two distinct groups of influenza A virus sialidases have been established, that differ in the flexibility of the '150-loop', providing a more open active site in the apo form of the group-1 compared to group-2 enzymes. In this study we show, through a multidisciplinary approach, that novel sialic acid-based derivatives can exploit this structural difference and selectively inhibit the activity of group-1 sialidases. We also demonstrate that group-1 sialidases from drug-resistant mutant influenza viruses are sensitive to these designed compounds. Moreover, we have determined, by protein X-ray crystallography, that these inhibitors lock open the group-1 sialidase flexible 150-loop, in agreement with our molecular modelling prediction. This is the first direct proof that compounds may be developed to selectively target the pandemic A/H1N1, avian A/H5N1 and other group-1 sialidase-containing viruses, based on an open 150-loop conformation of the enzyme.

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Figures

Figure 1
Figure 1. Chemical structures of anti-influenza viral drugs and influenza virus sialidase inhibitors.
Zanamivir (1), oseltamivir (2), oseltamivir carboxylate (3), Neu5Ac2en (4), 3-allyl-Neu5Ac2en (5) and 3-(p-tolyl)allyl-Neu5Ac2en (6).
Figure 2
Figure 2. Preparation of 3-allyl-Neu5Ac2en (5) and 3-(p-tolyl)allyl-Neu5Ac2en (6).
Reagents and conditions: (a) NBS, DMSO/H2O (2.5:1), −30 °C, 2 h (38% di-equatorial bromohydrin 8, 28% di-axial bromohydrin); (b) Bu3SnAll, AIBN, dry toluene, N2, 100 °C, 8 h (57%); (c) Ac2O, dry pyridine, DMAP, N2, room temperature, 16 h (95%); (d) AcCl, dry MeOH, dry DCM, 5 °C to room temperature, 48 h; (e) DBU, dry DCM, N2, room temperature, 8 h (91% over steps d and e, based on recovered starting material); (f) Grubbs' catalyst second generation, 4-methylstyrene, dry DCM, N2, 40 °C, 24 h (69%; 77% based on recovered starting material). (g) 1 M aq. NaOH, MeOH, 5 °C to room temperature, 12–16 h (5 and 6, 60%, based on recovered starting material, and 94%, respectively).
Figure 3
Figure 3. N8–5 complex.
(a) Superimposition of N8–inhibitor complexes of 3-allyl-Neu5Ac2en (5, green) and Neu5Ac2en (4, magenta; 2htr). (b) N8–5 complex with open 150-loop (5 in CPK format). The N8–5 complex maintains the open conformation of the 150-loop seen in the apo structure (a, b).
Figure 4
Figure 4. N8–6 complex.
(a) Superimposition of N8–inhibitor complexes of 3-(p-tolyl)allyl-Neu5Ac2en (6, cyan) and Neu5Ac2en (4, magenta; 2htr). (b) N8–6 complex with an open 150-loop (6 in CPK format). (c) N8–4 complex with a closed 150-loop (4 in CPK format). The N8–6 complex maintains an open conformation of the 150-loop seen in the apo structure (a, b), in contrast to the complex with 4 where the 150-loop is closed (c).
Figure 5
Figure 5. Superimposition of N8 structures.
Superimposition of the open 150-loop of N8–6 (cyan) and N8–5 (green), apo-N8 (pale orange; 2ht5) complexes, and the closed 150-loop of N8–4 (magenta; 2htr).
Figure 6
Figure 6. Electrostatic potential map of the N8–6 complex.
N8–6 complex showing electrostatic potential on the protein surface (red, negative; blue, positive; and white, neutral/hydrophobic). Neu5Ac2en (4), in magenta, is superimposed on 6.
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