RESUMEN
Hydrophobicity has proven to be an extremely useful parameter in small molecule drug discovery programmes given that it can be used as a predictive tool to enable rational design. For larger molecules, including peptoids, where folding is possible, the situation is more complicated and the average hydrophobicity (as determined by RP-HPLC retention time) may not always provide an effective predictive tool for rational design. Herein, we report the first ever application of partitioning experiments to determine the log D values for a series of peptoids. By comparing log D and average hydrophobicities we highlight the potential advantage of employing the former as a predictive tool in the rational design of biologically active peptoids.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Interacciones Hidrofóbicas e Hidrofílicas , Peptoides/química , Biblioteca de PéptidosRESUMEN
Peptoids are a promising class of antimicrobial agents with reported activities against a range of both Gram-positive and Gram-negative bacteria, fungi and most recently parasites. However, at present the available toxicity data is somewhat limited and as such rationally designing effective antimicrobial peptoids can be challenging. Herein, we present the toxicity profiling of a series of linear peptoids against mammalian cell lines (HaCaT and HepG2). The cytotoxicity of the peptoid library has then been correlated with their antibacterial properties against Gram-positive and Gram-negative bacteria and also to the hydrophobicity of the peptoid sequences. The work presented provides valuable data to aid in the future rational design of antimicrobial peptoids.
RESUMEN
Herein we report a practical synthetic route to the lasso peptide lassomycin () and C-terminal variant lassomycin-amide (). The biological evaluation of peptides and against Mycobacterium tuberculosis revealed that neither had any activity against this bacterium. This lack of biological activity has led us to propose that naturally occurring lassomycin may actually exhibit a standard lasso peptide threaded conformation rather than the previously reported unthreaded structure.
Asunto(s)
Amida Sintasas/química , Péptidos Cíclicos/química , Péptidos Cíclicos/síntesis química , Secuencia de Aminoácidos , Técnicas de Química Sintética , Conformación Molecular , Conformación ProteicaRESUMEN
Peptoids are a promising class of peptidomimetics that exhibit the key chemical and physical properties of peptides but without being hampered by susceptibility towards enzymatic degradation. Biologically active peptoids are often designed to be amphipathic in nature, consisting of hydrophobic monomers interspersed with either cationic lysine-type or arginine-type monomers. Access to amphipathic peptoids that contain both lysine-type and arginine-type monomers is highly desirable as it offers a route to further modulate the biological properties of this class of molecule. However, the lack of a suitable synthetic route to prepare mixed cationic peptoids has meant that their biological potential has remained almost largely unexplored. Herein, we present an efficient synthetic route that can be used to access novel cationic peptoids containing both lysine-type and arginine-type monomers within the same sequence.
Asunto(s)
Arginina/química , Lisina/química , Peptoides/química , Peptoides/síntesis química , Estructura MolecularRESUMEN
To measure the octapeptide angiotensin II (Ang II) in plasma, we developed a sensitive, specific assay that interfaces solid-phase extraction, HPLC, and RIA. A reversed-phase HPLC system involving isocratic elution at 38 degrees C with a volatile mobile phase of acetonitrile and the ion-pairing reagent heptafluorobutyric acid produced baseline separation of angiotensin peptides. Ang II was collected as a single fraction, concentrated by evaporation to dryness, and measured by RIA after resuspension in RIA buffer. Even including column washing between sample injections to prevent carryover of plasma constituents, two plasma extracts could be processed per hour by HPLC. Assay validation experiments demonstrated < 2% cross-reactivity with Ang II-related peptides; a 75% recovery from plasma at physiological concentrations of Ang II; intra- and interassay precision (CVs) of 6.2% and 10.3%, respectively; and a lower limit of quantification of 1.3 ng/L. Two clinical protocols designed to measure plasma Ang II concentration under basal and stimulated conditions confirmed the utility of the assay.