Synthesis of Cyclopeptides Analogues of Natural Products and Evaluation as Herbicides and Inhibitors of Cyanobacteria.

Natural products derived from plants or microorganisms have been considered as eco-friendly herbicides with application in crop protection. Several natural cyclopeptides have been reported as herbicides, while others have been identified as inhibitors of cyanobacteria. In this work, the syntheses of cyclotetrapeptides and cyclopentapeptides analogues of natural products were successfully performed by solid-phase peptide synthesis of their linear precursor and solution-phase macrolactamization. Four of the obtained peptides and cyclopeptides present phytotoxicity with more than 70% of radicle growth inhibition at 67 µg/mL. In addition, evaluation of 20 peptides and cyclopeptides, as inhibitors of cyanobacteria, rendered five active compounds that reduced the concentration of microcystins in the culture medium.

Rationally designed stapled peptides allosterically inhibit PTBP1-RNA-binding.

The diverse role of the splicing factor PTBP1 in human cells has been widely studied and was found to be a driver for several diseases. PTBP1 binds RNA through its RNA-recognition motifs which lack obvious pockets for inhibition. A unique transient helix has been described to be part of its first RNA-recognition motif and to be important for RNA binding. In this study, we further confirmed the role of this helix and envisioned its dynamic nature as a unique opportunity to develop stapled peptide inhibitors of PTBP1. The peptides were found to be able to inhibit RNA binding via fluorescence polarization assays and directly occupy the helix binding site as observed by protein crystallography. These cell-permeable inhibitors were validated in cellulo to alter the regulation of alternative splicing events regulated by PTBP1. Our study demonstrates transient secondary structures of a protein can be mimicked by stapled peptides to inhibit allosteric mechanisms.

Garbage in, garbage out: how reliable training data improved a virtual screening approach against SARS-CoV-2 MPro.

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence. Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy -performed in a large and diverse chemolibrary- complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening. Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 µM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12-20 µM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7-45 µM). Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known "garbage in, garbage out" machine learning principle.

Synthesis of Cyclotetrapeptides Analogues to Natural Products as Herbicides.

The synthesis of cyclotetrapeptides analogues of the natural products tentoxin and versicotide D was achieved in good yield by solid phase peptide synthesis (SPPS) of their linear precursors and solution phase cyclization. All the cyclopeptides and several open precursors were evaluated as herbicides. Five cyclopeptides and five lineal peptides showed a significant inhibition (>70%) of Ryegrass seed's radicle growth at 67 µg/mL. The evaluation at lower concentrations (4−11 µM) indicates two cyclopeptides analogs of tentoxin, which present one (N-Methyl-d-Phe), and two N-MeAA (N-Methyl-Ala and N-Methyl-Phe), respectively, as the most active of them, showing remarkable phytotoxic activity. In two cases, the open precursors are as active as their corresponding cyclopeptide. However, many linear peptides are inactive and their cyclization derivatives showed herbicidal activity. In addition, two cyclopeptide analogues of versicotide D showed more improved activity than the natural product. The results indicate that the peptide sequence, the amino acid stereochemistry and the presence of N-methyl group have important influence on the phytotoxic activity. Moreover, several compounds could be considered as lead candidates in the development of bioherbicides.

Three Methods for Peptide Cyclization Via Lactamization.

Lactamization is the key step in the synthesis of many compounds with macrocyclic structure. As the interest for these types of molecules grows in various fields such as drug discovery and nanomaterials, different methodologies to access them are being developed. Three different strategies to obtain cyclic peptides via lactamization are described in this chapter: solution-phase macrocyclization following solid-phase peptide synthesis (SPPS) of the linear precursor, SPPS and on-resin cyclization on the 2-chlorotrityl chloride (2-CTC) resin, and SPPS and on-resin cyclization by native chemical ligation on the amino-PEGA resin.

Colgajo bilobulado para reconstrucción de defectos por tumores nasales del tercio inferior / Bilobed flap for reconstruction of tumoral defects on the lower third of the nose

Introducción. Los defectos de cobertura en la región nasal secundarios a resecciones oncológicas deben ser cubiertos con tejido de las mismas características que el resecado, idealmente con tejido vascularizado adyacente. El colgajo bilobulado reúne las condiciones doble transposición, con una estructura y diseño que permite una adecuada distribución de las fuerzas de tensión a lo largo de su eje de rotación, evitando deformidades y excedente cutáneo generados por otros colgajos o cierre primario, respetando las unidades estéticas de la nariz. Método. Se presentan 48 casos clínicos en el periodo abril 2018 - abril 2020 describiendo la técnica de realización del colgajo bilobulado para la reconstrucción de secuelas de resección oncológica nasal por los diferentes tipos de tumores de piel. Para defectos de dorso nasal 26, punta nasal 14 y alares 8 casos. Resultados. La vitalidad de los colgajos fue de un 100%, 6 casos presentaron dehiscencia en extremo distal que requirió revisión. Adecuado resultados estéticos con similitud de textura y color de piel del colgajo. Cicatrices resultantes en área dadora y receptora ocultas en líneas de sombra. Disminución de complicaciones agregando resección triangular adicional. Conclusiones. Los defectos de tegumento en región nasal deben ser cubiertos por tejido vascularizado. Las resecciones de hasta 3 cm de diámetro pueden ser cubiertas con colgajos bilobulados adyacentes. El adecuado planeamiento de las cicatrices tanto en área dadora como receptora permite mejores resultados estéticos. Siempre deben tenerse en cuenta las regiones estéticas para obtener mejores resultados.

Background. Coverage defects in the nasal region secondary to oncological resections should be covered with tissue of the same characteristics as the resected, ideally with adjacent raised vascular tissue. The bilobed flap meets the conditions, is a double transposition flap, with a structure and design that allows an adequate distribution of the tension forces along its axis of rotation, avoiding deformities and excess skin generated by other flaps or primary closure. Respecting the aesthetic units of the nose. Methods. 48 clinical cases are presented in the period April 2010- April 2020 describing the technique of making the bilobed flap for the reconstruction of the sequelae of nasal oncological resection by the different types of skin tumors. For dorsal defects 26, nasal tip 14 and alares 8 cases. Results. The vitality of the flaps was 100%, 6 cases presented dehiscence in the distal end that required revision. Adequate aesthetic results with similarity of texture and skin color of the flap. Resulting scars in donor and recipient area hidden in shadow lines. Decrease complications by adding additional triangular resection. Conclusions. Integument defects in the nasal region should be covered by vascularized tissue. Resections up to 3 cm in diameter can be covered with adjacent bilobed flaps. The adequate planning of the scars in both the donor and recipient areas allows for better aesthetic results. Aesthetic regions should always be taken into account to obtain better results

Revistas Publindex de Ciencias Naturales: retos y perspectivas desde la bibliometría / Publindex Natural Sciences Magazines: challenges and perspectives from bibliometrics

Resumen Objetivo. Describir el comportamiento de las revistas de Ciencias Naturales indexadas en Publindex (2004-2020). Método. Se analizó un total de 68 revistas de Ciencias Naturales registradas en Publindex a través de la información registrada en bases de datos como Publindex y Google académico usando Harzing's Publish or Perish (POP) en una búsqueda combinada de título de la revista e ISSN. Las mediciones principales usadas fueron: indicadores de producción (# publicaciones, publicaciones por año e índice de productividad), citación (Índice H, Índice G, Índice E, Índice HC e Índice H5), informetría (concurrencia de palabras, clúster de palabras con mayor concurrencia (30)). Además, en lo relacionado con Publindex se identificaron revistas por área de conocimiento, por institución editora, categorización por año y perspectiva desde la fase 3 para la próxima medición. Resultados. En el índice bibliográfico nacional (IBN) hay 68 revistas en Ciencias Naturales, la mayor concentración se encuentra en el área de conocimiento Ciencias de la Tierra y Medioambientales (24%) y Ciencias biológicas (21%). Entre 2004 y 2014 se registró un promedio anual de 54 revistas categorizadas en el IBN, con el nuevo modelo de clasificación el promedio bajo a 19 por año entre 2017-2020. Las revistas que concentran la mayor cantidad de publicaciones en el total general son Revista Colombiana de Física (6,5%), Acta Biológica Colombiana (6,3%) y Revista Colombiana De Entomología (6,2%). Las revistas con el índice h más alto son Caldasia (H=43), Revista de La Academia Colombiana de Ciencias Exactas y Físicas y Naturales (H=37). Luego de la simulación para los resultados de la Convocatoria Publindex 2020 en la fase 3, las categorías que registran aumento son A1 del (9%) y C (14%). Conclusiones. El 37% de las revistas en Ciencias Naturales tienen alta posibilidad de ser categorizadas en el IBN 2020. Se registra un descenso en la cantidad de publicaciones de las revistas y en las citas desde 2017 y 2018 respectivamente. Las revistas NOVA, Acta Biológica Colombiana, Biota Colombiana, Revista Lasallista de Investigación, Revista de La Academia Colombiana de Ciencias Exactas, Físicas y Naturales y Caldasia registran los índices bibliométricos (H, G, HC, D) más altos, además, están categorizadas y proyectan seguirlo en 2020.

Abstract Objective. To describe the behavior of the Natural Sciences journals indexed in Publindex (2004-2020). Methods. A total of 68 Natural Science journals registered in Publindex were analyzed through information registered in databases such as Publindex and Google academic using Harzing's Publish or Perish (POP) in a combined search of journal title and ISSN. The main measures used were: production indicators (# publications, publications per year and productivity index), citation (H index, G index, E index, HC index and H5 index), reporttry (word concurrence, cluster of words with highest concurrence (30)). In addition, in relation to Publindex, journals were identified by area of knowledge, by publishing institution, categorization by year and perspective from phase 3 for the next measurement. Results. In the national bibliographic index (IBN) there are 68 journals in Natural Sciences, the highest concentration is in the knowledge area of Earth and Environmental Sciences (24%) and Biological Sciences (21%). Between 2004 and 2014, an annual average of 54 journals categorized in the IBN was registered, with the new classification model the average being below 19 per year between 2017-2020. The journals that concentrate the greatest number of publications in the general total are Revista Colombiana de Física (6.5%), Acta Biológica Colombiana (6.3%) and Revista Colombiana De Entomología (6.2%). The journals with the highest h index are Caldasia (H=43), Revista de La Academia Colombiana de Ciencias Exactas y Físicas y Naturales (H=37). After the simulation for the results of the Call Publindex 2020 in phase 3, the categories that register an increase are A1 (9%) and C (14%). Conclusions. 37% of the journals in Natural Sciences have a high possibility of being categorized in the IBN 2020. There is a decrease in the number of journal publications and citations since 2017 and 2018 respectively. The journals NOVA, Acta Biológica Colombiana, Biota Colombiana, Revista Lasallista de Investigación, Revista de La Academia Colombiana de Ciencias Exactas, Físicas y Naturales and Caldasia register the highest bibliometric indices (H, G, HC, D), besides, they are categorized and plan to follow it in 2020.

First total synthesis of versicotide A, B and C.

The syntheses of versicotides A-C, natural products containing anthranilic acid and NMe-Ala, were achieved by solid phase peptide synthesis on 2-chlorotrityl resin followed by solution phase macrocyclization. Using an oxyma additive, the difficult coupling reactions to the deactivated aromatic amine of o-aminobenzoic acid, were performed in high yield, avoiding anthranilic rearrangements or side reactions.

On-resin synthesis of cyclic peptides via tandem N-to-S acyl migration and intramolecular thiol additive-free native chemical ligation.

On-resin intramolecular native chemical ligation (NCL) assisted by N-ethylcysteine using Fmoc/SPPS to obtain cyclic peptides is described. N-terminal cysteine-containing peptides were subjected to NCL conditions leading to cyclization-cleavage reactions and consecutive S → N shift, rendering cyclic peptides in good yields and purities. The compounds were evaluated against P. falciparum 3D7.

A prospective comparative study between differential moments and miniscrews in anchorage control.

The purpose of this study was to measure the efficacy of anchorage control between differential moments mechanics and temporary anchorage devices in a clinical trial. Forty-six patients requiring extraction of maxillary first premolars were allocated into 2 treatment groups. The differential moments group (G1) received a nickel titanium (NiTi) intrusion arch and a 150g NiTi closing coil spring for separate canine retraction, followed by a continuous mushroom loop archwire for the retraction of the incisors. The TAD group (G2) received one miniscrew placed between maxillary second premolars and first molars with a 150 g NiTi closing coil spring connecting the miniscrew to a hook placed in the archwire between the lateral incisor and canine. Lateral cephalograms were taken before (T1) and after incisor retraction (T2). The ratio of molar protraction to incisor retraction was calculated and intragroup and intergroup changes in upper lip, maxillary incisor and molar position were analyzed by paired and independent t-tests. Twenty-eight patients were analyzed after 18 patients did not receive the intervention, were lost to follow-up, or discontinued treatment. The ratio of molar protraction to incisor retraction in G1 was 0.44 and in G2 was -0.11, which was significantly different. There was a statistically significant change in upper lip from T1 to T2 but no difference between the two groups. Moreover, there was a significant distal molar tipping and lingual incisor tipping in G2. There is a significant difference in the amount of anchorage control using differential moments mechanics compared to TADs. Although statistically significant retraction of upper lip was observed in both groups, there was no significant difference between the two groups.

Tratamiento de la infección por herpes simple: efecto de la procaína infiltrada sobre las lesiones recurrentes del herpes labial / Effect of submucosal infiltration of recurrent herpes labialis lesions

El objetivo del estudio fue establecer el efecto de la procaína infiltrada en el tiempo de cicatrización de las lesiones recurrentes del herpes simple labial. Se incluyeron 30 pacientes, 20 mujeres y 30 hombres. Todos presentaban lesiones establecidas de herpes labial (estado vesicular) con máximo dos días de evolución y 22 presentaron haber presentado lesiones recurrentes previas. Los pacientes fueron evaluados clínicamente y la información referente a la historia y evolución de las lesiones fue registrada en un formulario. Las lesiones se infiltraron con 1.8 ml de procaína al 1 por ciento y se hizo un seguimiento cada 24 horas hasta la cicatrización de las mismas. Esta información fue comparada con el comportamiento clínico y tiempo de cicatrización habitual de las lesiones relatado por los pacientes, además con la comparación de con los resultados de otros estudios los cuales evalúan diferentes agentes terapéuticos para las lesiones recurrentes del herpes labial.