Synthesis and antiviral activity of HCV NS3/4A peptidomimetic boronic acid inhibitors.

A new series of NS3/4A protease boronic acid inhibitors is described. The compounds show good biochemical potency and cellular activity. The peptidomimetic inhibitors were evaluated against proteases from different HCV genotypes and clinically relevant NS3/4A mutants. Compound 28 displayed subnanomolar to single digit nanomolar potencies in the enzymatic assays and an EC50 of 25 nM in the replicon cell-based assay.

Bicyclic cyanothiazolidines as novel dipeptidyl peptidase 4 inhibitors.

The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.

First-in-class pan caspase inhibitor developed for the treatment of liver disease.

A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.

Boro-norleucine as a P1 residue for the design of selective and potent DPP7 inhibitors.

Dipeptide-based inhibitors with C-substituted (alkyl or aminoalkyl) alpha-amino acids in the P2 position and boro-norleucine (boro-Nle) in the P1 position were synthesized. Relative to boro-proline, boro-Nle as a P1 residue was shown able to significantly dial out DPP4, FAP, DPP8, and DPP9 activity. Dab-boro-Nle (4g) proved to be the most selective and potent DPP7 inhibitor with a DPP7 IC50 value of 480 pM.

High-resolution functional proteomics by active-site peptide profiling.

Characterization and functional annotation of the large number of proteins predicted from genome sequencing projects poses a major scientific challenge. Whereas several proteomics techniques have been developed to quantify the abundance of proteins, these methods provide little information regarding protein function. Here, we present a gel-free platform that permits ultrasensitive, quantitative, and high-resolution analyses of protein activities in proteomes, including highly problematic samples such as undiluted plasma. We demonstrate the value of this platform for the discovery of both disease-related enzyme activities and specific inhibitors that target these proteins.

In vivo caries formation in enamel following argon laser irradiation and combined fluoride and argon laser treatment: a clinical pilot study.

OBJECTIVE: This in vivo pilot study investigated the role of argon laser irradiation and combined fluoride and argon laser treatment in accelerated natural caries development in sound enamel surfaces beneath plaque-retentive orthodontic bands. METHOD AND MATERIALS: Five patients (3 female, 2 male, ages 19 to 28 years) requiring tooth extraction prior to orthodontic treatment, participated in the study. Buccal surfaces were treated with either: (1) argon laser (250 mW for 10 seconds, ARGO-MOD); (2) topical fluoride (0.5% fluoride ion, Thera-Flur-N) followed by argon lasing; or (3) no treatment (control). Orthodontic bands with plaque-retentive slots on buccal surfaces were placed on the teeth slated for extraction (n = 14). Following a minimum of 5 weeks of intraoral exposure, the teeth were extracted for laboratory analysis. The teeth underwent serial longitudinal sectioning (12 sections per tooth). The sections were imbibed in water, and lesion depths were determined with each section, using polarized light microscopy. Comparisons were made among treatment groups (analysis of variance, Duncan's multiple range test for paired samples). RESULTS: Mean lesion depths were: 261 +/- 24 microm for the no treatment control group (n = 84 sections); 147 +/- 18 microm for the argon laser group (n = 24 sections); and 99 +/- 12 microm for the fluoride and argon laser group (n = 60 sections). Both the argon laser (44%) and the fluoride and argon laser groups (62%) had significant lesion depth reductions compared to controls. The addition of fluoride treatment prior to argon lasing resulted in a 32% reduction in lesion depth compared to argon laser treatment alone. CONCLUSIONS: Within this clinical pilot study, in vivo natural caries formation was affected significantly by a single exposure to low fluence argon laser irradiation. Topical fluoride treatment in combination with argon lasing provided an even greater degree of resistance against in vivo enamel caries development. A simple technique for reducing the caries susceptibility of enamel may be a clinical reality.