Advances in the Structure-Based Design of the Influenza A Neuraminidase Inhibitors

Abstract

Since 2003, highly pathogenic H5N1 influenza viruses have been the cause of large-scale death in poultry and the subsequent infection and death of over 140 humans. At present, there are only three licensed anti-Influenza drugs namely Relenza (Zanamivir - ZMV), Tamiflu (Oseltamivir - OTV) and Amantadine/Rimantadine. The latter targets the M2 ion channel whereas the other compounds target neuraminidase (NA) and were designed through structure-based enzyme inhibitor programmes. Some structural knowledge of the Influenza neuraminidase is now known, due to remarkable advances in crystallographic techniques. The structure of H5N1 NA is particularly attractive because it offers new opportunities for drug design. Besides a profound impact that structural biology has had on understanding the Influenza virus and the rational design of antivirals, computational methods are now a viable partner to experiment in designing NA inhibitors. We herein discuss the development of current neuraminidase inhibitors, the emergence of resistance to them, and recent research progress towards the development of new inhibitors.

Influenza neuraminidase

“…Peramivir was briefly licensed for emergency use during the swine-origin H1N1 epidemic in an injectable formulation for patients on ventilators and is currently completing clinical trials, and several other backbones are being tested as well as further derivatives of zanamivir. Several recent reviews describe these new developments 3,5,6,66–69 .…”

Design Of Novel Anti-Influenza Drugs That Circumvent Oseltamivir Resistance: A Critical Perspective

“…The 'open' conformation of the crystal structure of H5N1 NA in complex with OTV (PDB ID: 2HU0) was used to rationalize the molecular mechanism of oseltamivir resistance using molecular docking simulations [4][5][6]. It was demonstrated that the 150-cavity can be exploited for designing the more potent inhibitors of H5N1 NA [4,7] in the same way as experimentally proposed [2].…”

“…It was demonstrated that the 150-cavity can be exploited for designing the more potent inhibitors of H5N1 NA [4,7] in the same way as experimentally proposed [2]. The relevance of these observations [4][5][6][7] was questioned by pointing out both that an improper initial structure (PDB ID: 2HU0) was used and that a 'closed' conformation of the N1:OTV co-crystal structure is more appropriate for such studies [8].…”

“…It was demonstrated that the 150-cavity can be exploited for designing the more potent inhibitors of H5N1 NA [4,7] in the same way as experimentally proposed [2]. The relevance of these observations [4][5][6][7] was questioned by pointing out both that an improper initial structure (PDB ID: 2HU0) was used and that a 'closed' conformation of the N1:OTV co-crystal structure is more appropriate for such studies [8]. Even though the discrepancies between the theoretical [5] and experimental [9] structures of the His274Tyr NA:OTV protein:ligand complexes were initially observed, the inclusion of protein flexibility, especially in the region of 150-loop, in the molecular docking protocol successfully fixed the glitch *Corresponding author: Dr. Petar M Mitrasinovic, Belgrade Institute of Science and Technology, 11060 Belgrade, Serbia, E-mail: petar.mitrasinovic@yahoo.com [10,11].…”

“…Moreover, the possibility of designing more potent OTV derivatives than OTV itself was illustrated by both employing the 'open' conformation of the NA crystal structure (PDB ID: 2HU0) and taking advantage of the presence of the 150-cavity nearby the N1 NA active site [13]. It was concluded that the 'open' form crystal structure of 2HU0 provides a novel and reliable structural basis for rational drug design against influenza virus [13], thus speaking in favor of all the previous studies [4][5][6][7] being based upon the experimental proposal of Russell et al [2]. This conclusion was substantiated by molecular dynamics simulations [12,14] focusing on the functional behavior of 150-loop in N1 from avian H5N1.…”