Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling

The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates

Hybridization properties of base-modified oligonucleotides within the double and triple helix motif

In this review we describe the influence of modified nucleobases in order to understand the changes they introduce in double and triple helix forming oligomers with the aim to study their potential therapeutic use in the antisense/antigene/ribozyme field. The hybridization properties of the studied modified oligomers depend on the structure of the modified nucleoside, the number of modifications, the selected sequence and the location of the modified nucleoside along the sequence. Unfortunately, most available information is based on melting point determination, eventually CD experiments and only in a few cases on X-ray and NMR studies which makes it difficult to put forward general rules for predicting modified nucleic acid structures. On the other hand, several of the described base modifications allow us to select new oligonucleotides with improved properties in the different application fields. (C) Elsevier, Paris.status: publishe

Synthesis and conformational behavior of purine and pyrimidine beta-D-threo-hex-3'enopyranosyl nucleosides

Based on the previous observation that anhydrohexitol nucleosides may exert antiviral activity, we have synthesized a series of beta-D-threo-hex-3'-enopyranosyl nucleosides starting from 1,5-anhydro-4,6-O-benzylidene-2-O-p-toluoyl-D-glucitol. These nucleosides adopt a predominant H-0(1) conformation with a pseudo axially oriented base moiety. This conformational behaviour can be explained by favorable pi-sigma* interactions, a gauche effect and hydrogen bond interactions. The alternative H-1(0) conformation is disfavored due to pseudo-1,3-diaxial interactions. Copyright (C) 1996 Elsevier Science Ltdstatus: publishe

The Strength of the Anomeric Effect in Adenosine, Guanosine, and in Their 2′-Deoxy Counterparts is Medium-Dependent

In nucleosides, the anomeric effect (AE) (i.e. stereoelectronic n(O4′)fσ* C1′-N9 interactions) places the aglycon in the pseudoaxial orientation in the N-type conformation (2′-exo-3′-endo), whereas the inherent steric effect of the nucleobase opposes the AE by its tendency to take up pseudoequatorial orientation in the S-type conformation (2′-endo-3′-exo). This means that the actual energetic contribution of the AE of an N-or a C-aglycon in a nucleoside can be determined by subtracting the steric effect of the N-or C-aglycon from the total effect of the aglycon on the drive of N a S pseudorotational equilibrium. The ∆G°of N a S pseudorotational equilibrium among a set of various neutral C-and N-nucleosides showed that the relatively most thermodynamically stabilized S-type conformer is found in 9-deazaadenosine in which 9-deazaadenin-9-yl at C1′ takes up the relatively most favored pseudoequatorial orientation between pH 8.8-12.0 (∆H°) -14.2 kJ/mol) as a result of the exclusive steric control for the drive (∆H°) of N a S pseudorotational equilibrium. 9-Deazaadenin-9-yl at C1′ therefore serves as the best reference point for subtraction of the steric effect of the adenin-9-yl or guanin-9-yl in adenosine (A), guanosine (G), and in their 2′-deoxy counterparts (dA and dG). Since the electronic character of adenin-9-yl or guanin-9-yl changes from the neutral to the protonated (or deprotonated in case of guanin-9-yl) state as the pH of the medium changes (refs 1p, 1s), the work reported here shows for the first time that the intrinsic AE of A, G, dA, and dG are indeed pD-dependent. The tunable strength of the AE can vary from 23.4 to 17.7 kJ/mol in A from pD 1.2 to 7.0, 37.5 to 15.6 kJ/mol in G from pD 0.6 to 11.6, 18.0 to 14.8 kJ/mol in dA from pD 0.9 to 7.0, 20.7 to 13.8 kJ/mol in dG from pD 0.9 to 11.6

Synthesis and conformational analysis of 1,5-anhydro-2,4-dideoxy-D-mannitol nucleosides

1,5-Anhydro-4,6-O-benzylidene-D-glucitol was used as starting material for the synthesis of 1,5-anhydro-2,4-dideoxy-D-mannitol nucleosides with an adenine and uracil base moiety. The compound with a purine base was obtained by direct nucleophilic substitution of a triflate. The pyrimidine nucleoside could be obtained by epoxide opening followed by inversion of configuration at the 3'-position. Both nucleosides adopt a C1 conformation with an axial base moiety.status: publishe

A situation-aware mobile system to support fire brigades in emergency situations

In a firefighter emergency mission it is essential for the members of a fire brigade to get an intelligent and reliable overview of the complete situation, presented according to the role of each member. In this paper we report on the design and development of a system to support a fire brigade on site with a set of mobile services that offers a role-based focus+context user interface. It provides the required overview over the emergency situation according to the user task and context, while life-saving information is emphasized. The implementation of a context-rule-based decision module enhances the visualization of required information. Interaction with the user interface is designed for use in the wild; which in this case comes down to providing a "fat finger" interface that allows firemen to interact with the user interface on site with his gloves on

Protection of 2,6-diaminopurine 2'-deoxyriboside

Protection of both amine moieties of 2,6-diaminopurine 2'-deoxyriboside as a dimethylformamidine group did not proove feasable, while protection with a phenoxyacetyl group afforded only a mono-protected analogue 5. This analogue can be incorporated into oligonucleotides without difficulties. However, oligonucleotides with diaminopurine substituted for adenine did not yield more stable duplexes for the two sequences tested here.status: publishe

Synthesis and properties of O-beta-D-ribofuranosyl-(1''-2 ')-adenosine-5''-O-phosphate and its derivatives

The synthesis of O-beta -D-ribofuranosyl-(1"-2')-adenosine-5"-O-phosphate and its suitably protected derivative for oligonucleotide synthesis have been developed.status: publishe