Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions.

Short half-lives in circulation and poor transport across the blood-brain barrier limit the utility of cytokines and growth factors acting as receptor agonists. Here we show that surrogate receptor agonists with longer half-lives in circulation and enhanced transport rates across the blood-brain barrier can be generated by genetically inserting macrocyclic peptide pharmacophores into the structural loops of the fragment crystallizable (Fc) region of a human immunoglobulin. We used such 'lasso-grafting' approach, which preserves the expression levels of the Fc region and its affinity for the neonatal Fc receptor, to generate Fc-based protein scaffolds with macrocyclic peptides binding to the receptor tyrosine protein kinase Met. The Met agonists dimerized Met, inducing biological responses that were similar to those induced by its natural ligand. Moreover, lasso-grafting of the Fc region of the mouse anti-transferrin-receptor antibody with Met-binding macrocyclic peptides enhanced the accumulation of the resulting Met agonists in brain parenchyma in mice. Lasso-grafting may allow for designer protein therapeutics with enhanced stability and pharmacokinetics.

Sarcoma de Ewing extraesquelético de rápido crecimiento en paciente de 2 años: Reporte de caso / Fast growing extraskeletal Ewing sarcoma in a 2 year old patient: Case report

El sarcoma de Ewing forma parte de una familia de tumores que se caracterizan por presentar translocaciones que involucran al gen EWS y algún miembro de la familia ETS que posee un dominio de unión al ADN. Se presenta el caso de un paciente de dos años de edad con una masa cervical de crecimiento rápido que por compresión local comprometió estructuras nerviosas manifestándose inicialmente con un retardo en el neurodesarrollo. Se diagnosticó Sarcoma de Ewing/Tumor neuroectodérmico primitivo por biopsia. Este es un tipo de tumor raro con una presentación inusual a nivel cervical; el cual debe tenerse en cuenta al momento de evaluar pacientes con masas cervicales en especial las de crecimiento rápido con el fin de dar un tratamiento preciso y oportuno.

Ewing's sarcoma is part of a family of tumors that is characterized by translocations that involve the EWS gene and a member of the ETS family that has a DNA binding domain. The case of a two-year-old patient who was admitted in our institution because of a rapidly growing cervical mass associated to neurodevelopment setback and functional gradual loss due to nerve compression. Ewing's sarcoma / primitive neuroectodermal tumor was diagnosed by biopsy. This is a rare type of tumor with an unusual presentation in this location; which should be taken into account when assessing a patient with cervical masses, especially those of rapid growth in order to provide an accurate and opportune treatment for improving outcomes.

Caracterización matemática de la unión de la proteína PfNBP-1 al eritrocito mediante la aplicación de la probabilidad y entropía / Mathematical characterization of binding between PfNBP-1 protein and erythrocyite by applying probability and entropy

Objetivo: Estudiar la proteína Plasmodium falciparum Normocyte Binding Protein-1 (PfNBP-1), partiendo de un método de caracterización físico-matemática desarrollado previamente para péptidos de alta unión del merozoito de malaria al eritrocito. Materiales y métodos: Se tomaron 21 péptidos con tamaño de 20 aminoácidos no sobrelapados de los cuales dos son de alta unión, se cuantificó la frecuencia de aparición de los 20 aminoácidos esenciales en cada posición y se calculó la probabilidad, sumatoria de probabilidad y la entropía con el objetivo de diferenciar matemáticamente los péptidos de alta y baja unión. Posteriormente se calcularon los mismos valores para péptidos teóricos análogos, en los que fueron cambiados por glicinas los aminoácidos críticos confirmados experimentalmente. Resultados: Los péptidos de PfNBP-1 comprobados experimentalmente de alta unión, presentaron valores de probabilidad, sumatoria de probabilidad y entropía ubicados dentro del macroestado de unión y sus péptidos teóricos análogos presentaron resultados que se diferenciaban cada vez más del macroestado de unión a medida que se reemplazaban aminoácidos críticos por glicinas. En cuanto a las secuencias de no unión de PfNBP-1, se encontró que los valores calculados son diferentes a los asociados al macroestado de unión, comprobando que en el 100 % de casos estudiados es posible diferenciar los péptidos de no unión y alta unión matemáticamente. Conclusiones: La probabilidad y la entropía permiten caracterizar adecuadamente los péptidos de alta unión de PfNBP-1, y evidenciar el orden matemático subyacente al proceso de unión de proteínas de malaria.

Objective: To study the Plasmodium falciparum Normocyte Binding Protein-1 (PfNBP-1) based on a of physicalmathematical characterization method previously developed for high binding peptides of malaria merozoite to erythrocyte. Materials and methods: 21 non overlapped peptides with size of 20 amino acids, including two of high binding were taken; the frequency of occurrence of the 20 essential amino acids in each position was quantified and probability, summation of probability and entropy were calculated in order to mathematically differentiate high and low binding peptides. Later the same values were calculated for theoretical analogs peptides, where the critical amino acids confirmed experimentally were changed by glycine. Results: The experimentally validated high binding peptides of PfNBP-1 showed values of probability, summation of probability and entropy located within the binding macrostate peptides and their theoretical analogues peptides presented results that differed increasingly of the binding macrostate as critical amino acids were replaced by glycine. For the PfNBP-1 sequences of non-binding, it was found that the calculated values are different from those associated with the macrostate of binding and it was verified that in 100% of studied cases it is possible to mathematically differentiate binding and non-binding peptides. Conclusions: The probability and entropy allow to adequately characterize the high-binding peptides of PfNBP-1 and show the mathematical order underlying the process of protein binding of malaria to the erythrocyte.