Structural basis for a class of nanomolar influenza A neuraminidase inhibitors.

The influenza virus neuraminidase (NA) is essential for the virus life cycle. The rise of resistance mutations against current antiviral therapies has increased the need for the development of novel inhibitors. Recent efforts have targeted a cavity adjacent to the catalytic site (the 150-cavity) in addition to the primary catalytic subsite in order to increase specificity and reduce the likelihood of resistance.

Exploring the interactions of unsaturated glucuronides with influenza virus sialidase.

A series of C3 O-functionalized 2-acetamido-2-deoxy-Δ⁴-β-D-glucuronides were synthesized to explore noncharge interactions in subsite 2 of the influenza virus sialidase active site. In complex with A/N8 sialidase, the parent compound (C3 OH) inverts its solution conformation to bind with all substituents well positioned in the active site. The parent compound inhibits influenza virus sialidase at a sub-μM level; the introduction of small alkyl substituents or an acetyl group at C3 is also tolerated.

Synthesis and evaluation of novel 3-C-alkylated-Neu5Ac2en derivatives as probes of influenza virus sialidase 150-loop flexibility.

Novel 3-C-alkylated-Neu5Ac2en derivatives have been designed to target the expanded active site cavity of influenza virus sialidases with an open 150-loop, currently seen in X-ray crystal structures of influenza A virus group-1 (N1, N4, N5, N8), but not group-2 (N2, N9), sialidases. The compounds show selectivity for inhibition of H5N1 and pdm09 H1N1 sialidases over an N2 sialidase, providing evidence of the relative 150-loop flexibility of these sialidases. In a complex with N8 sialidase, the C3 substituent of 3-phenylally-Neu5Ac2en occupies the 150-cavity while the central ring and the remaining substituents bind the active site as seen for the unsubstituted template.

Conservation of a crystallographic interface suggests a role for β-sheet augmentation in influenza virus NS1 multifunctionality.

The effector domain (ED) of the influenza virus virulence factor NS1 is capable of interaction with a variety of cellular and viral targets, although regulation of these events is poorly understood. Introduction of a W187A mutation into the ED abolishes dimer formation; however, strand-strand interactions between mutant NS1 ED monomers have been observed in two previous crystal forms. A new condition for crystallization of this protein [0.

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

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.

Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity.

The tenovins and cambinol are two classes of sirtuin inhibitor that exhibit antitumor activity in preclinical models. This report describes modifications to the core structure of cambinol, in particular by incorporation of substituents at the N1-position, which lead to increased potency and modified selectivity. These improvements have been rationalized using molecular modeling techniques.

Crystal structure of the NanB sialidase from Streptococcus pneumoniae.

The Streptococcus pneumoniae genomes encode up to three sialidases (or neuraminidases), NanA, NanB and NanC, which are believed to be involved in removing sialic acid from host cell surface glycans, thereby promoting colonization of the upper respiratory tract. Here, we present the crystal structure of NanB to 1.7 A resolution derived from a crystal grown in the presence of the buffer Ches (2-N-cyclohexylaminoethanesulfonic acid).

Crystal structure of the bacterial ribosomal decoding site complexed with amikacin containing the gamma-amino-alpha-hydroxybutyryl (haba) group.

Amikacin is the 4,6-linked aminoglycoside modified at position N1 of the 2-deoxystreptamine ring (ring II) by the L-haba group. In the present study, the crystal structure of a complex between oligonucleotide containing the bacterial ribosomal A site and amikacin has been solved at 2.7 A resolution.

Interactions of designer antibiotics and the bacterial ribosomal aminoacyl-tRNA site.

The X-ray crystal structures for the complexes of three designer antibiotics, compounds 1, 2, and 3, bound to two models for the ribosomal aminoacyl-tRNA site (A site) at 2.5-3.0 Angstroms resolution and that of neamine at 2.

Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding.

The crystal structures of six complexes between aminoglycoside antibiotics (neamine, gentamicin C1A, kanamycin A, ribostamycin, lividomycin A and neomycin B) and oligonucleotides containing the decoding A site of bacterial ribosomes are reported at resolutions between 2.2 and 3.0 A.

The complex of a designer antibiotic with a model aminoacyl site of the 30S ribosomal subunit revealed by X-ray crystallography.

The ribosome is an important target for aminoglycoside antibiotics; however, the clinical effectiveness of aminoglycosides has diminished due to bacterial resistance mechanisms. Here we report the X-ray structure of a novel synthetic aminoglycoside bound to the A site of the ribosome, its target for manifestation of activity. The structure validates the in silico design paradigms for the antibiotic and reveals the molecular interactions made by this novel antibiotic in prokaryotes.

Stepwise adaptations of citrate synthase to survival at life's extremes. From psychrophile to hyperthermophile.

The crystal structure of citrate synthase from the thermophilic Archaeon Sulfolobus solfataricus (optimum growth temperature = 85 degrees C) has been determined, extending the number of crystal structures of citrate synthase from different organisms to a total of five that span the temperature range over which life exists (from psychrophile to hyperthermophile). Detailed structural analysis has revealed possible molecular mechanisms that determine the different stabilities of the five proteins. The key to these mechanisms is the precise structural location of the additional interactions.