RESUMO
A new orbitide named ribifolin was isolated and characterized from Jatropha ribifolia using mass spectrometry, NMR spectroscopy, quantitative amino acid analysis, molecular dynamics/simulated annealing, and Raman optical activity measurements and calculations. Ribifolin (1) and its linear form (1a) were synthesized by solid-phase peptide synthesis, followed by evaluation of its antiplasmodial and cytotoxicity activities. Compound 1 was moderately effective (IC50 = 42 µM) against the Plasmodium falciparum strain 3D7.
Assuntos
Antimaláricos , Jatropha/química , Peptídeos Cíclicos , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Testes de Sensibilidade Parasitária , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , Peptídeos Cíclicos/farmacologia , Extratos Vegetais/química , Técnicas de Síntese em Fase SólidaRESUMO
A cyclic peptide, jatrophidin I, was isolated from the latex of Jatropha curcas L. Its structure was elucidated by extensive 2D NMR spectroscopic analysis, with additional conformational studies performed using Molecular Dynamics/Simulated Annealing (MD/SA). Jatrophidin I had moderate protease inhibition activity when compared with pepstatin A; however, the peptide was inactive in antimalarial, cytotoxic and antioxidant assays.
Assuntos
Jatropha/química , Látex/química , Peptídeos Cíclicos/isolamento & purificação , Ácido Aspártico Proteases/antagonistas & inibidores , Brasil , Ensaios de Seleção de Medicamentos Antitumorais , Modelos Moleculares , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pepstatinas/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologiaRESUMO
Thrombin is a serine proteinase that plays a fundamental role in coagulation. In this study, we address the effects of ligand site recognition by alpha-thrombin on conformation and energetics in solution. Active site occupation induces large changes in secondary structure content in thrombin as shown by circular dichroism. Thrombin-D-Phe-Pro-Arg-chloromethyl ketone (PPACK) exhibits enhanced equilibrium and kinetic stability compared to free thrombin, whose difference is rooted in the unfolding step. Small-angle X-ray scattering (SAXS) measurements in solution reveal an overall similarity in the molecular envelope of thrombin and thrombin-PPACK, which differs from the crystal structure of thrombin. Molecular dynamics simulations performed with thrombin lead to different conformations than the one observed in the crystal structure. These data shed light on the diversity of thrombin conformers not previously observed in crystal structures with distinguished catalytic and conformational behaviors, which might have direct implications on novel strategies to design direct thrombin inhibitors.