Synthesis of Cylcotetrapeptides Analogues to Natural Products as Herbicides

The synthesis of cyclotetrapeptides analogues of the natural productos 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 Rye grass seed’s radicle growth at 67 μg/mL. The evaluation at lower concentration (4-11 M), indicates two cyclopeptides analogs of tentoxin, which present one (N-Methyl-D-Phe), and two NMe -AA (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 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.Agencia Nacional de Investigación e InnovaciónUniversidad de la República. Comisión Sectorial de Investigación Científic

Synthesis of Cylcotetrapeptides Analogues to Natural Products as Herbicides

The synthesis of cyclotetrapeptides analogues of the natural productos 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 Rye grass seed’s radicle growth at 67 μg/mL. The evaluation at lower concentration (4-11 M), indicates two cyclopeptides analogs of tentoxin, which present one (N-Methyl-D-Phe), and two NMe -AA (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 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.Agencia Nacional de Investigación e InnovaciónUniversidad de la República. Comisión Sectorial de Investigación Científic

Risk factors for postoperative depression in 150 subjects treated for drug-resistant focal epilepsy.

Objective.The primary goal was to identify risk factors for post-surgical depression in subjects operated on for drug-resistant epilepsy. Secondary goals were to confirm the high rate of depression in subjects suffering from epilepsy (prior to surgery) and to look for first post-surgical depressive episode.Methods.Case series study of 150 subjects surgically treated for partial epilepsy (side of surgery: 72 right, 78 left; site of surgery: 97 Unilobar Temporal, 17 Unilobar Frontal, 14 Posterior, 22 Multilobar). All subjects routinely had three psychiatric evaluations: before surgery (baseline) and at 6 and 12 months after surgery. Psychiatric diagnoses were made according to DSM-IV-TR criteria. Bivariate (Fisher exact test and Kruskal–Wallis rank sum test) and multivariate (logistic regression model fitting) analyses were performed.Results.Thirty-three (22%) subjects had post-surgical depressive episodes, 31 of them in the first 6 months. Fourteen out of 33 experienced depression for the first time. Post-surgical depressive episodes are not associated with gender, outcome on seizures, side/site of surgical resection, histological diagnosis, psychiatric diagnoses other than depression. Depressive episodes before surgery and older age at surgery time are risk factors for post-surgical depression (p = 0.0001 and 0.01, respectively, at logistic regression analysis). No protective factors were identified.Conclusions.Our data show that lifetime depressive episodes and older age at surgery time are risk factors for post-surgery depression. Moreover, a prospective study could be useful in order to assess whether depression is really a consequence of surgery

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

Síntesis de péptidos y ciclopéptidos como posibles aplicaciones de la Biotecnología. Agentes antimaláricos, herbicides o inhibidores de cianobacterias

Desde hace más de una década, nuestro grupo ha trabajado en la síntesis de ciclopéptidos análogos a productos naturales potencialmente bioactivos. En este trabajo se presenta la síntesis de Péptidos utilizando la metodología Fmoc de Síntesis de Péptidos en Fase Sólida y la macrociclación tanto en la resina como en solución. Los compuestos fueron obtenidos con buenos rendimientos y excelentes purezas. Dentro de el grupo de los ciclohexapéptidos, encontramos actividades muy relevantes contra el parásito Plasmodium falciparum, causante de la malaria. Por otro lado, se sintetizaron los productos naturales Versicotides A-F y dos de ellos mostraron muy buenas actividades como herbicidas e inhibidores del crecimiento de cianobacterias. Además, los ciclotetrapéptidos análogos a tentoxin mostraron actividades herbicidas.Agencia Nacional de Investigación e InnovaciónUniversidad de la República. Comisión Sectorial de Investigación Científic

Síntesis de Ciclopéptidos análogos a productos naturales como potenciales herbicidas e inhibidores de cianobacterias

Una de las grandes problemáticas de Uruguay respecto a las prácticas agrícolas es el continuo aumento de la resistencia de las malezas frente a herbicidas comerciales. El uso indiscriminado de herbicidas, lleva a un aumento de sustancias inorgánicas en el medio que, sumado al calentamiento global y otros factores ambientales, promueven la floración de cianobacterias productoras de toxinas, en diversos cursos de agua. El trabajo presentado comprende la síntesis de ciclopéptidos análogos a productos naturales, utilizando la técnica de Síntesis de Péptidos en Fase Sólida (SPPS) y macrociclación en solución. A los diferentes compuestos sintetizados se les evaluó su acción frente a la germinación, desarrollo foliar y longitud radicular en agar, utilizando semillas de Raigrás (Lollium multiflorum). También fue evaluada su acción frente a la inhibición del crecimiento de cianobacterias y la concentración de microcistinas del medio de cultivo. Se obtuvieron 13 ciclopéptidos y sus precursores con rendimientos y purezas de muy buenos a aceptables; dos de ellos con interesante actividad herbicida y con acción inhibitoria del crecimiento de cianobacterias.Agencia Nacional de Investigación e InnovaciónUniversidad de la República. Comisión Sectorial de Investigación Científic

Synthesis of a Microcystis aeruginosa predicted metabolite with antimalarial activity.

The synthesis of a Microcystis aeruginosa predicted metabolite analog of aerucyclamide B was performed. This hexacyclopeptide was obtained from three heterocyclic building blocks by a convergent macrocycle-assembly methodology. The compound exhibited good in vitro antiplasmodial activity (IC(50): 0.18 μM, K1, cholorquine resistant strain)

The Dream as a Model for Psychosis: An Experimental Approach Using Bizarreness as a Cognitive Marker

Many previous observers have reported some qualitative similarities between the normal mental state of dreaming and the abnormal mental state of psychosis. Recent psychological, tomographic, electrophysiological, and neurochemical data appear to confirm the functional similarities between these 2 states. In this study, the hypothesis of the dreaming brain as a neurobiological model for psychosis was tested by focusing on cognitive bizarreness, a distinctive property of the dreaming mental state defined by discontinuities and incongruities in the dream plot, thoughts, and feelings. Cognitive bizarreness was measured in written reports of dreams and in verbal reports of waking fantasies in 30 schizophrenics and 30 normal controls. Seven pictures of the Thematic Apperception Test (TAT) were administered as a stimulus to elicit waking fantasies, and all participating subjects were asked to record their dreams upon awakening. A total of 420 waking fantasies plus 244 dream reports were collected to quantify the bizarreness features in the dream and waking state of both subject groups