The identification of potent, selective, and bioavailable cathepsin S inhibitors

Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3.     

Concurrent niche and neutral processes in the competition-colonization model of species coexistence

The importance of neutral dynamics is contentiously debated in the ecological literature. This debate focuses on neutral theory's assumption of fitness equivalency among individuals, which conflicts with stabilizing fitness that promotes coexistence through niche differentiation. I take advantage of competition-colonization trade-offs between species of aquatic micro-organisms (protozoans and rotifers) to show that equalizing and stabilizing mechanisms can operate simultaneously. Competition trials between species with similar colonization abilities were less likely to result in competitive exclusion than for species further apart. While the stabilizing mechanism (colonization differences) facilitates coexistence at large spatial scales, species with similar colonization abilities also exhibited local coexistence probably due to fitness similarities allowing weak stabilizing mechanisms to operate. These results suggest that neutral- and niche-based mechanisms of coexistence can simultaneously operate at differing temporal and spatial scales, and such a spatially explicit view of coexistence may be one way to reconcile niche and neutral dynamics.     

Bat echolocation calls: adaptation and convergent evolution

Bat echolocation calls provide remarkable examples of 'good design' through evolution by natural selection. Theory developed from acoustics and sonar engineering permits a strong predictive basis for understanding echolocation performance. Call features, such as frequency, bandwidth, duration and pulse interval are all related to ecological niche. Recent technological breakthroughs have aided our understanding of adaptive aspects of call design in free-living bats. Stereo videogrammetry, laser scanning of habitat features and acoustic flight path tracking permit reconstruction of the flight paths of echolocating bats relative to obstacles and prey in nature. These methods show that echolocation calls are among the most intense airborne vocalizations produced by animals. Acoustic tracking has clarified how and why bats vary call structure in relation to flight speed. Bats using broadband echolocation calls adjust call design in a range-dependent manner so that nearby obstacles are localized accurately. Recent phylogenetic analyses based on gene sequences show that particular types of echolocation signals have evolved independently in several lineages of bats. Call design is often influenced more by perceptual challenges imposed by the environment than by phylogeny, and provides excellent examples of convergent evolution. Now that whole genome sequences of bats are imminent, understanding the functional genomics of echolocation will become a major challenge.     

The molecular pruning of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen

To identify the pharmacophore of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen (PSMA), a small analog library was designed and screened for inhibitory potency against PSMA. The design of the lead inhibitor was based upon N-acyl derivatives of endogenous substrate folyl-gamma-Glu and incorporates a phosphoramidate group to interact with the PSMA catalytic zinc atoms. The scope of the analog library was designed to test the importance of various functional groups to the inhibitory potency of the lead phosphoramidate. The IC(50) for the lead phosphoramidate inhibitor was 35 nM while the IC(50) values for the analog library presented a range from 0.86 nM to 4.1 microM. Computational docking, utilizing a recently solved X-ray crystal structure of the recombinant protein, along with enzyme inhibition data, was used to propose a pharmacophore model for the PSMA active site.     

The distribution pattern of centipedes in four primeval forests of central Slovakia

We investigated the distribution pattern of centipedes (Chilopoda) in four primeval forests of the western Carpathians, central Slovakia. The forests are located in two different mountain ranges (Kremnické vrchy and Pol’ana Mountains), which are exposed on either the southern (Boky, Rohy) or northern slopes (Pol’ana, Badín). In these forests, the influence of coarse woody debris (CWD) on centipede distribution was studied, by distinguishing sampling sites on the forest floor, close to CWD (c-CWD) and distant from CWD (d-CWD). In total, we collected 2,706 individuals from 20 species of centipedes. Average species richness and number of individuals per forest ranged from 8 to 12 species/m² and from 244 to 486 individuals/m². The oak forests on south facing slopes harboured several species, which did not occur in the more northern exposed fir-beech forests. Number of species as well as individuals, however, varied more within than between individual forests. Increase of species number and density was mainly caused by CWD and was more pronounced on the southern slopes (P<0.001), characterized by high temperatures and low precipitation, than on the northern slopes (n.s. to P<0.01), characterized by low temperatures and high precipitation. It was found that CWD did not generally increase (species) diversity.     

3-Mercaptopropionic acids as efficacious inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa)

A novel series of cyclic potent, selective, small molecule, thiol-based inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) and the crystal structures of TAFIa inhibitors bound to porcine pancreatic carboxypeptidase B are described. Three series of cyclic arginine and lysine mimetic inhibitors vary significantly in their selectivity against other human basic carboxypeptidases, carboxypeptidase N and carboxypeptidase B. (-)2a displays TAFIa IC50 = 3 nM and 600-fold selectivity against CPN. Inhibition of TAFIa with (rac)2a resulted in dose dependent acceleration of human plasma clot lysis in vitro and was efficacious as an adjunct to tPA in an in vivo rabbit jugular vein thrombolysis model.     

ERbeta ligands. Part 5: synthesis and structure-activity relationships of a series of 4'-hydroxyphenyl-aryl-carbaldehyde oxime derivatives

A series of 4'-hydroxyphenyl-aryl-carbaldehyde oximes (5b) was prepared and found to have high affinity (4nM) and modest selectivity (39-fold) for estrogen receptor-beta (ERbeta). Substitution of one of the core rings of the scaffold based around these novel ligands further expanded our knowledge in the quest toward achieving high affinity and selectivity for ERbeta. An X-ray co-crystal of structure 11 revealed that the oxime moiety was mimicking the C-ring of genistein, as previously predicted by SAR and docking studies.     

The discovery of potent, selective, and orally bioavailable hNK1 antagonists derived from pyrrolidine

SAR studies on amides, ureas, and vinylogous amides derived from pyrrolidine led to the discovery of several potent hNK(1) antagonists. One particular vinylogous amide (45b) had excellent potency, selectivity, pharmacokinetic profile, and functional activity in vivo. An in vivo rhesus macaque brain receptor occupancy PET study for compound 45b revealed an estimated Occ(90) approximately 300 ng/ml.     

Genetic population structure of the endemic fourline wrasse (Larabicus quadrilineatus) suggests limited larval dispersal distances in the Red Sea

The connectivity among marine populations is determined by the dispersal capabilities of adults as well as their eggs and larvae. Dispersal distances and directions have a profound effect on gene flow and genetic differentiation within species. Genetic homogeneity over large areas is a common feature of coral reef fishes and can reflect high dispersal capability resulting in high levels of gene flow. If fish larvae return to their parental reef, gene flow would be restricted and genetic differentiation could occur. Larabicus quadrilineatus (Labridae) is considered as an endemic fish species of the Red Sea and Gulf of Aden. The juveniles of this species are cleaner fish that feed on ectoparasites of other fishes. Here, we investigated the genetic population structure and gene flow in L. quadrilineatus among five locations in the Red Sea to infer connectivity among them. To estimate genetic diversity, we analysed 369 bp of 237 mitochondrial DNA control region sequences. Haplotype and nucleotide diversities were higher in the southern than in the northern Red Sea. Analysis of molecular variance (amova) detected the highest significant genetic variation between northern and central/southern populations (Phi(CT) = 0.01; P < 0.001). Migration analysis revealed a several fold higher northward than southward migration, which could be explained by oceanographic conditions and spawning season. Even though the Phi(ST) value of 0.01 is rather low and implies a long larval dispersal distance, estimates based on the isolation-by-distance model show a very low mean larval dispersal distance (0.44-5.1 km) compared to other studies. In order to enable a sustainable ornamental fishery on the fourline wrasse, the results of this study suggest that populations in the northern and southern Red Sea should be managed separately as two different stocks. The rather low larval dispersal distance of about 5 km needs to be considered in the design of marine protected areas to enable connectivity and self-seeding.     

Preparation of tetrahydroimidazo[2,1-a]isoquinolines and their use as inhibitors of gastric acid secretion

A series of novel tetrahydroimidazo[2,1-a]isoquinolines was prepared based on a hetero Diels–Alder reaction between an enamine and 1,2,4-triazine as key step. A structure–activity relationship was established focussing on the influence of the substitution pattern in position 3 and 6 of the heterocycle on antisecretory activity, lipophilicity, and pK_a value. Potent inhibitors of the gastric acid pump were identified.