RESUMEN
Three types of chemical entities, namely, small organic molecules (organics), peptides, and biologics, are mainly used as drug candidates for the treatment of various diseases. Even though the peptide drugs are known since 1920 in association with the clinical use of insulin, only a limited number of peptides are currently used for therapeutics due to various disadvantages associated with them such as limited serum and blood stability, oral bioavailability, and permeability. Since, through chemical modifications and structure tuning, many of these limitations can be overcome, peptide-based drugs are gaining attention in pharmaceutical research. As of today, there are more than 60 peptide-based drugs approved by FDA, and over 150 peptides are in the advanced clinical studies. In this book chapter, the peptide-based lead compounds and drugs available for treating various viral diseases and their advantages and disadvantages when compared to small molecules drugs are discussed.
Asunto(s)
Productos Biológicos , Virosis , Antivirales/uso terapéutico , Humanos , Insulina , Péptidos , Virosis/tratamiento farmacológicoRESUMEN
The most important natural α- and 310 -helices are stabilized by unidirectional intramolecular hydrogen bonds along the helical cylinder. In contrast, we report here on 12/10-helical conformations with alternately changing hydrogen-bond directionality in sequences of α,γ-hybrid peptides P1-P5 [P1: Boc-Ala-Aic-Ala-Aic-COOH; P2: Boc-Leu-Aic-Leu-Aic-OEt; P3: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe; P4: Boc-Ala-Aic-Ala-Aic-Ala-Aic-Ala-OMe; P5: Boc-Leu-Aic-Leu-Aic-Leu-Aic-Leu-Aic-Aib-OMe; Aic=4-aminoisocaproic acid, Aib=2-aminoisobutyric acid] composed of natural α-amino acids and the achiral γ4,4 -dimethyl substituted γ-amino acid Aic in solution and in single crystals. The helical conformations are stabilized by alternating iâi+3 and iâi-1 intramolecular hydrogen bonds. The experimental data are supported by ab initio MO calculations. Surprisingly, replacing the natural α-amino acids of the sequence by the achiral dialkyl amino acid Ac6 c [P6: Boc-Ac6 c-Aic-Ac6 c-Aic-Ac6 c-Aic-Ac6 c-Aic-Ac6 c-CONHMe; Ac6 c = 1-aminocyclohexane-1-carboxylic acid] led to a 12-helix with unidirectional hydrogen bonds showing an entirely different backbone conformation. The results presented here emphasize the influence of the structure of the α-amino acid residues in dictating the helix types in α,γ-hybrid peptide foldamers and demonstrate the consequences for folding of small structural variations in the monomers.
Asunto(s)
Aminoácidos/química , Péptidos/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Estructura Secundaria de Proteína , Teoría CuánticaRESUMEN
Here, novel 12-helices in α,γ-hybrid peptides composed of achiral α-aminoisobutyric acid (Aib) and 4-aminoisocaproic acid (Aic, doubly homologated Aib) monomers in 1:1 alternation are reported. The 12-helices were indicated by solution and crystal structural analyses of tetra- and heptapeptides. Surprisingly, single crystals of the longer nonapeptide displayed two different helix types: the novel 12-helix and an unprecedented 15/17-helix. Quantum chemical calculations on both helix types in a series of continuously lengthened Aib/Aic-hybrid peptides confirm that the 12-helix is more stable than the 15/17-helix in shorter peptides, whereas the 15/17-helix is more stable in longer sequences. Thus, the coexistence of both helix types can be expected within a definite range of sequence lengths. The novel 15/17- and 12-helices in α,γ-hybrid peptides with 5â1 and 4â1 hydrogen-bonding patterns, respectively, can be viewed as backbone-expanded analogues of native α- and 310 -helices.
Asunto(s)
Ácido Aminocaproico/química , Ácidos Aminoisobutíricos/química , Péptidos/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Conformación Proteica en Hélice alfa , Pliegue de Proteína , EstereoisomerismoRESUMEN
The impact of geometrically constrained cis α,ß-unsaturated γ-amino acids on the folding of α,γ-hybrid peptides was investigated. Structure analysis in single crystals and in solution revealed that the cis carbon-carbon double bonds can be accommodated into the 12-helix without deviation from the overall helical conformation. The helical structures are stabilized by 4â1 hydrogen bonding in a similar manner to the 12-helices of ß-peptides and the 310 helices of α-peptides. These results show that functional cis carbon-carbon double bonds can be accommodated into the backbone of helical peptides.
Asunto(s)
Carbono/química , Péptidos/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Resonancia Magnética Nuclear Biomolecular , Estructura Secundaria de Proteína , EstereoisomerismoRESUMEN
Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic ß-amyloid (Aß) peptides produced by ß- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). ß-secretase inhibitors reduce Aß levels, but mechanism-based side effects arise because they also inhibit ß-cleavage of non-amyloid substrates like Neuregulin. We report that ß-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of ß-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by ß-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal ß-secretase by an endosomally targeted ß-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. ß-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/metabolismo , Oligopéptidos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animales , Ácido Aspártico Endopeptidasas/química , Ácido Aspártico Endopeptidasas/metabolismo , Células Cultivadas , Endocitosis , Endosomas/metabolismo , Aparato de Golgi/metabolismo , Humanos , Células Madre Pluripotentes Inducidas , Cinética , Ratones , Simulación de Dinámica Molecular , Neurregulina-1/química , Neurregulina-1/metabolismo , Oligopéptidos/química , Procesamiento Proteico-Postraduccional , Transporte de Proteínas , Proteolisis , Especificidad por SustratoRESUMEN
The synthesis and utilization of novel thiostatines (ß-SH-substituted γ-amino acids) in the design of backbone-disulfide-stabilized ß-hairpin mimetics, solution conformations of hybrid ß-hairpins and Cys-disulfide-stabilized α-peptide analogue, their thiol exchange, and proteolytic stability are investigated. The results suggest that thiostatines can be used to design proteolytically stable water-soluble ß-hairpin mimetics without deviating from overall ß-hairpin conformation.
Asunto(s)
Aminoácidos/síntesis química , Disulfuros/química , Quininógenos/síntesis química , Péptidos/química , Aminoácidos/química , Cisteína/química , Enlace de Hidrógeno , Quininógenos/química , Estructura Molecular , Conformación Proteica , Estructura Secundaria de ProteínaRESUMEN
The solution and solid state conformations of a designed ß-hairpin containing functionalizable α,ß-unsaturated γ-amino acids at the antiparallel ß-strands and a single step transformation to its saturated γ-peptide analogue are studied.
Asunto(s)
Péptidos/química , Péptidos/síntesis química , Aminoácidos/química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Conformación Proteica , EstereoisomerismoRESUMEN
The crystal structures of five model peptides Piv-Pro-Gly-NHMe (1), Piv-Pro-betaGly-NHMe (2), Piv-Pro-betaGly-OMe (3), Piv-Pro-deltaAva-OMe (4) and Boc-Pro-gammaAbu-OH (5) are described (Piv: pivaloyl; NHMe: N-methylamide; betaGly: beta-glycine; OMe: O-methyl ester; deltaAva: delta-aminovaleric acid; gammaAbu: gamma-aminobutyric acid). A comparison of the structures of peptides 1 and 2 illustrates the dramatic consequences upon backbone homologation in short sequences. 1 adopts a type II beta-turn conformation in the solid state, while in 2, the molecule adopts an open conformation with the beta-residue being fully extended. Piv-Pro-betaGly-OMe (3), which differs from 2 by replacement of the C-terminal NH group by an O-atom, adopts an almost identical molecular conformation and packing arrangement in the solid state. In peptide 4, the observed conformation resembles that determined for 2 and 3, with the deltaAva residue being fully extended. In peptide 5, the molecule undergoes a chain reversal, revealing a beta-turn mimetic structure stabilized by a C-H...O hydrogen bond.
Asunto(s)
Aminoácidos/química , Modelos Moleculares , Péptidos/química , Cristalización , Enlace de Hidrógeno , Conformación Proteica , Difracción de Rayos XRESUMEN
A new class of polypeptide helices in hybrid sequences containing alpha-, beta-, and gamma-residues is described. The molecular conformations in crystals determined for the synthetic peptides Boc-Leu-Phe-Val-Aib-betaPhe-Leu-Phe-Val-OMe 1 (betaPhe: (S)-beta3-homophenylalanine) and Boc-Aib-Gpn-Aib-Gpn-OMe 2(Gpn: 1-(aminomethyl)cyclohexaneacetic acid) reveal expanded helical turns in the hybrid sequences (alpha alphabeta)n and (alphagamma)n. In 1, a repetitive helical structure composed of C14 hydrogen-bonded units is observed, whereas 2 provides an example of a repetitive C12 hydrogen-bonded structure. Using experimentally determined backbone torsion angles for the hydrogen-bonded units formed by hybrid sequences, we have generated energetically favorable hybrid helices. Conformational parameters are provided for C11, C12, C13, C14, and C15 helices in hybrid sequences.