Conservation planning for retention, not just protection.

Most protected area (PA) planning aims to improve biota representation within the PA system, but this does not necessarily achieve the best outcomes for biota retention across regions when we also consider habitat loss in areas outside the PA system. Here, we assess the implications that different PA expansion strategies can have on the retention of species habitat across an entire region. Using retention of forest habitat for Colombia's 550 forest-dependent bird species as our outcome variable, we found that when a minimum of 30% of each species' habitat was included in the PA system, a pattern of PA expansion targeting areas at highest deforestation risk (risk-prevention) led to the retention, on average, of 7.2% more forest habitat per species by 2050 than did a pattern that targeted areas at lowest risk (risk-avoidance). The risk-prevention approach cost more per km2 of land conserved, but it was more cost-effective in retaining habitat in the landscape (50%-69% lower cost per km2 of avoided deforestation). To have the same effectiveness preventing habitat loss in Colombia, the risk-avoidance approach would require more than twice as much protected area, costing three times more in the process. Protected area expansion should focus on the contributions of PAs to outcomes not only within PA systems themselves, but across entire regions.

La mayor parte de la planificación de áreas protegidas (AP) tiene como objetivo mejorar la representación de la biota dentro del sistema de AP, pero esto no necesariamente logra los mejores resultados para la retención de biota a nivel de paisaje cuando también consideramos la pérdida de hábitat en áreas fuera del sistema de AP. Aquí evaluamos las implicaciones que diferentes estrategias de expansión de AP pueden tener en la retención del hábitat de las especies en toda una región. Utilizando la retención de hábitat forestal para las 550 especies de aves dependientes de bosque de Colombia como nuestra variable de resultado, encontramos que cuando un mínimo del 30% del hábitat de cada especie es incluido en el sistema de AP, se observó que un patrón de expansión de AP dirigido a áreas con mayor riesgo de deforestación (prevención de riesgos) condujo a la retención, en promedio, de un 7.2% más de hábitat por especie para 2050 que un patrón enfocado en áreas con menor riesgo (evasión de riesgos). El enfoque de prevención de riesgos costó más por km2 de tierra conservada, pero fue más rentable para retener el hábitat en el paisaje (entre un 50% y un 69% menos costo por km2 de deforestación evitada). Para tener la misma eficacia en la prevención de la pérdida de hábitat en Colombia, el enfoque de evasión de riesgos requeriría más del doble de área protegida, lo que costaría tres veces más en el proceso. La expansión de las AP debería centrarse en las contribuciones de las AP a los resultados no sólo dentro de los propios sistemas de AP, sino en regiones enteras.

Generation of new synthetic scaffolds using framework libraries selected and refined via medicinal chemist synthetic expertise.

With the expansion in the application of library methods in medicinal chemistry and chemical biology there is a growing need for improved technology for the design of novel templates that are well suited for the synthesis of libraries targeted toward specific subsets of protein families. In this report, we delineate an improved stepwise general method that is well suited for this purpose. This process uses virtual framework libraries to identify frameworks that rigidly match specific aspects of a ligand's bioactive conformation. The resulting frameworks can then be ranked and sequentially modified by a combination of computational scripts and human derived expertise, in order to develop rational proposals for new combinatorial templates or new sets of potential ligands.

Application of a novel design paradigm to generate general nonpeptide combinatorial templates mimicking beta-turns: synthesis of ligands for melanocortin receptors.

We report the further application of a novel approach to template and ligand design by the synthesis of agonists of the melanocortin receptor. This design method uses the conserved structural data from the three-dimensional conformations of beta-turn peptides to design rigid nonpeptide templates that mimic the orientation of the main chain C-alpha atoms in a peptide beta-turn. We report details on a new synthesis of derivatives of template 1 that are useful for the synthesis of exploratory libraries. The utility of this technique is further exemplified by several iterative rounds of high-throughput synthesis and screening, which result in new partially optimized nonpeptide agonists for several melanocortin receptors.

An in vivo approach to structure activity relationship analysis of peptide ligands.

PURPOSE: The goals in this study were several-fold. First, to optimize the in vivo phage display methodology by incorporating phage pharmacokinetic properties, to isolate peptides that target the brain microvasculature, and then to build focused libraries to obtain structure activity relationship information in vivo to identify the optimal targeting motif. MATERIALS AND METHODS: The blood pharmacokinetics of filamentous and T7 phage were evaluated to choose the optimal platform. A randomized peptide library with a motif CX(10)C was constructed in T7 phage and used for in vivo panning. Focused peptide libraries around each structural element of the brain-specific peptide were constructed to perform kinetic structure activity relationship (kSAR) analysis in vivo. To determine potential function, sepsis was induced in mice by LPS administration and four hours later the effect of GST-peptide on adhesion of rhodamine-labelled lymphocytes or CFDA-labelled platelets to pial microvasculature was observed by intravital microscopy. RESULTS: The blood phamacokinetics of T7 was rapid (half-life of 12 min) which aids the clearance of non-specific phage. In vivo panning in brain enriched for isolates expressing the motif CAGALCY. Kinetic analysis of focused libraries built around each structural element of the peptide provided for rapid pharmacophore mapping. The computer modeling data suggested the peptide showed similarities to peptide mimetics of adhesion molecule ligands. GST-CAGALCY but not GST control protein was able to inhibit the rolling and adhesion of labeled platelets to inflamed pial vasculature. GST-CAGALCY had no effect on lymphocyte adhesion. CONCLUSIONS: Incorporating normal blood phamacokinetics of T7 phage into in vivo phage display improves the ability to recover targeting peptide motifs and allows effective lead optimization by kSAR. This approach led to the isolation of a brain-specific peptide, CAGALCY, which appears to function as an effective antagonist of platelet adhesion to activated pial microvasculature.