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1.
J Am Chem Soc ; 142(7): 3489-3498, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31977205

RESUMO

The use of helical hexapeptides to establish a surface dipole layer on a TiO2 substrate, with the goal of influencing the energy levels of a coadsorbed chromophore, is explored. Two helical hexapeptides, synthesized from 2-amino isobutyric acid (Aib) residues, were protected at the N-terminus with a carboxybenzyl group (Z) and at the C-terminus carried either a carboxylic acid or an isophthalic acid (Ipa) anchor group to form Z-(Aib)6-COOH or Z-(Aib)6-Ipa, respectively. Using a combination of vibrational and photoemission spectroscopies, bonding of the two peptides to TiO2 surfaces (either nanostructured or single-crystal TiO2(110)) was found to be highly dependent on the anchor group, with Ipa establishing a monolayer much more efficiently than COOH. Furthermore, a monolayer of Z-(Aib)6-Ipa on TiO2(110) was exposed for different binding times to a solution of a zinc tetraphenylporphyrin (ZnTPP) derivative terminated with an Ipa anchor group (ZnTPP-P-Ipa). Photoemission spectroscopy revealed that ZnTPP-P-Ipa partly displaced Z-(Aib)6-Ipa, forming a coadsorbed monolayer on the oxide surface. The presence of the peptide molecular dipole shifted the HOMO levels of the ZnTPP group to lower energy by ∼300 meV, in accordance with a simple parallel plate capacitor model. These results suggest that a mixed-layer approach, involving coadsorption of a strong molecular dipole compound with a chromophore, is a versatile method to shift the energy levels of such chromophores with respect to the band edges of the substrate.


Assuntos
Ácidos Aminoisobutíricos/química , Oligopeptídeos/química , Titânio/química , Modelos Moleculares , Nanoestruturas/química , Oligopeptídeos/síntese química , Ligação Proteica , Dobramento de Proteína , Estrutura Secundária de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier
2.
Chem Asian J ; 14(23): 4408-4414, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670907

RESUMO

Molecular chirality is ubiquitous in nature. The natural biopolymers, proteins and DNA, preferred a right-handed helical bias due to the inherent stereochemistry of the monomer building blocks. Here, we are reporting a rare co-existence of left- and right-handed helical conformations and helix-terminating property at the C-terminus within a single molecule of α,γ-hybrid peptide foldamers composed of achiral Aib (α-aminoisobutyric acid) and 3,3-dimethyl-substituted γ-amino acid (Adb; 4-amino-3,3-dimethylbutanoic acid). At the molecular level, the left- and right-handed helical screw sense of α,γ-hybrid peptides are representing a macroscopic tendril perversion. The pronounced helix-terminating behaviour of C-terminal Adb residues was further explored to design helix-Schellman loop mimetics and to study their conformations in solution and single crystals. The stereochemical constraints of dialkyl substitutions on γ-amino acids showed a marked impact on the folding behaviour of α,γ-hybrid peptides.


Assuntos
Peptídeos/química , Ácidos Aminoisobutíricos/química , Cristalografia por Raios X , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica em alfa-Hélice , Estereoisomerismo
3.
Biochemistry ; 58(44): 4398-4407, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31625391

RESUMO

γ-Secretase is a membrane-embedded aspartyl protease complex with presenilin as the catalytic component that cleaves within the transmembrane domain (TMD) of >90 known substrates, including the amyloid precursor protein (APP) of Alzheimer's disease. Processing by γ-secretase of the APP TMD produces the amyloid ß-peptide (Aß), including the 42-residue variant (Aß42) that pathologically deposits in the Alzheimer brain. Complex proteolysis of APP substrate by γ-secretase involves initial endoproteolysis and subsequent carboxypeptidase trimming, resulting in two pathways of Aß production: Aß49 → Aß46 → Aß43 → Aß40 and Aß48 → Aß45 → Aß42 → Aß38. Dominant mutations in APP and presenilin cause early onset familial Alzheimer's disease (FAD). Understanding how γ-secretase processing of APP is altered in FAD is essential for elucidating pathogenic mechanisms in FAD and developing effective therapeutics. To improve our understanding, we designed synthetic APP-based TMD substrates as convenient functional probes for γ-secretase. Installation of the helix-inducing residue α-aminoisobutyric acid provided full TMD helical substrates while also facilitating their synthesis and increasing the solubility of these highly hydrophobic peptides. Through mass spectrometric analysis of proteolytic products, synthetic substrates were identified that were processed in a manner that reproduced physiological processing of APP substrates. Validation of these substrates was accomplished through mutational variants, including the installation of two natural APP FAD mutations. These FAD mutations also resulted in increased levels of formation of Aß-like peptides corresponding to Aß45 and longer, raising the question of whether the levels of such long Aß peptides are indeed increased and might contribute to FAD pathogenesis.


Assuntos
Secretases da Proteína Precursora do Amiloide/química , Precursor de Proteína beta-Amiloide/química , Fragmentos de Peptídeos/química , Doença de Alzheimer/genética , Sequência de Aminoácidos , Ácidos Aminoisobutíricos/química , Precursor de Proteína beta-Amiloide/síntese química , Precursor de Proteína beta-Amiloide/genética , Espectrometria de Massas , Mutação , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/genética , Conformação Proteica em alfa-Hélice , Proteólise
4.
Mol Pharm ; 16(11): 4542-4550, 2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31596588

RESUMO

Replacement therapy with tumor suppressive microRNA (TS-miRNA) might be the next-generation oligonucleotide therapy; however, a novel drug delivery system (DDS) is required. Recently, we developed the cell-penetrating peptide, model amphipathic peptide with α-aminoisobutyric acid (MAP(Aib)), as a carrier for oligonucleotide delivery to cells. In this study, we examined whether a modified MAP(Aib) analogue, MAP(Aib)-cRGD, could be a DDS for TS-miRNA replacement therapy. MIR145-5p, a representative TS-miRNA especially in colorectal cancer, was selected. The MAP(Aib)-cRGD dose was adjusted for MIR145-5p delivery to cells using peripheral blood mononuclear cells and degradation analysis. AlexaFluor488-labeled MIR145-5p incorporation into cells and negative regulation of MIR145-5p-targeting genes demonstrated MAP(Aib)-cRGD's functionality as a miRNA DDS. Treating MIR145-5p with MAP(Aib)-cRGD also revealed various anticancer effects, such as cell viability, invasion inhibition, and apoptosis induction in WiDr cells. Altogether, these findings suggest that MAP(Aib)-cRGD could be a DDS for TS-miRNA replacement therapy, but in vivo investigations are required.


Assuntos
Ácidos Aminoisobutíricos/química , Peptídeos Penetradores de Células/química , MicroRNAs/química , Peptídeos Cíclicos/química , Linhagem Celular , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , MicroRNAs/farmacologia , Oligonucleotídeos/química
5.
Amino Acids ; 51(9): 1247-1257, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31350614

RESUMO

Somatostatin (SST) is an endogenous cyclic tetradecapeptide hormone that exerts multiple biological activities via a family of five receptors. BIM-23052 (DC-23-99) D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2 is a linear SST analog with established in vitro GH-inhibitory activity and high affinity to sstr5, sstr3 and sstr2. The different SSTR subtypes are expressed in different tissues and in some tumor cells. Based on this finding, a series of new analogs of BIM-23052 with expected antitumor activity have been synthesized. The Thr at position 6 in BIM-23052 was replaced by the conformationally hindered Tle, Aib, Ac5c and Ac6c of the new analogs. The peptides were synthesized by standard solid-phase peptide chemistry methods, Fmoc strategy. The cytotoxic effects of the compounds were tested in vitro against a panel of tumor cell lines: HT-29, MDA-MB-23, Hep-G2, HeLa and the normal human diploid cell line Lep-3. All five somatostatin receptor subtypes were modeled and docking was performed to determine the binding affinity of the analogs. The new peptides exhibited different concentration-dependent antiproliferative effect on the tumor cell lines after 24 h of treatment. The compound 3B (Aib6) demonstrated the most pronounced antiproliferative effects on HepG-2 cells with the IC50 = 0.01349 nM. Docking confirmed that all compounds bind well to SST receptors with preference to sstr3 and sstr5, which is most probably the reason for the observed biological effects.


Assuntos
Aminoácidos/química , Antineoplásicos/química , Somatostatina/análogos & derivados , Aminoácidos Cíclicos/química , Ácidos Aminoisobutíricos/química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Ácidos Cicloexanocarboxílicos/química , Cicloleucina/química , Células HT29 , Células HeLa , Humanos , Simulação de Acoplamento Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Receptores de Somatostatina/química , Somatostatina/química , Somatostatina/farmacologia , Relação Estrutura-Atividade
7.
J Phys Chem A ; 123(19): 4178-4187, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-30973730

RESUMO

Aminoisobutyric acid (Aib) oligomers are known to form racemic mixtures of enantiomeric left- and right-handed structures. The introduction of a chiral cap converts the enantiomeric structures into diastereomers that, in principle, afford spectroscopic differentiation. Here, we screen different C-terminal caps based on a model Aib dipeptide using double resonance laser spectroscopy in the gas phase to record IR and UV spectra of individual conformations present in the supersonic expansion: NH-benzyl (NHBn) as a reference structure because of its common use as a fluorophore in similar studies, NH- p-fluorobenzyl (NHBn-F), and α-methylbenzylamine (AMBA). For both the NHBn and NHBn-F caps, a single conformer is observed, with infrared spectra assignable to an enantiomeric pair of type II/II' ß-turns in these molecules lacking a chiral center. The higher oscillator strength of the NHBn-F cap enabled UV-UV hole burning, not readily accomplished with the NHBn cap. The AMBA-capped structure, with its chiral center, produced two unique conformers, one of which was a nearly identical left-handed type II ß-turn, while the minor conformer is assigned to a C7-C7 sequential double ring, which is an emergent form of a 27-ribbon. Although not observed, the type II' ß-turn diastereomer, with opposite handedness, is calculated to be 11 kJ/mol higher in energy, a surprisingly large difference. This destabilization is attributed primarily to steric interference between the C-terminal acyl oxygen of the peptide and the chirality-inducing methyl of the AMBA group. Last, computational evidence indicates that the use of an N-terminal aromatic cap hinders the formation of a 310-helix in Ac-Aib2 dipeptides.


Assuntos
Ácidos Aminoisobutíricos/química , Dipeptídeos/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Modelos Moleculares , Conformação Proteica , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
8.
Nat Commun ; 10(1): 1807, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-31000719

RESUMO

L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.


Assuntos
Sistema y+ de Transporte de Aminoácidos/química , Ácidos Aminoisobutíricos/química , Proteínas de Bactérias/química , Sistema y+ de Transporte de Aminoácidos/genética , Sistema y+ de Transporte de Aminoácidos/metabolismo , Ácidos Aminoisobutíricos/metabolismo , Animais , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Camelídeos Americanos , Cristalografia por Raios X , Células HeLa , Humanos , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Anticorpos de Cadeia Única/química , Especificidade por Substrato
9.
Gen Comp Endocrinol ; 278: 58-67, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107140

RESUMO

Insect kinins modulate aspects of diuresis, digestion, development, and sugar taste perception in tarsi and labellar sensilla in mosquitoes. They are, however, subject to rapid biological degradation by endogenous invertebrate peptidases. A series of α-aminoisobutyric (Aib) acid-containing insect kinin analogs incorporating sequences native to the Aedes aegypti mosquito aedeskinins were evaluated on two recombinant kinin invertebrate receptors stably expressed in cell lines, discovering a number of highly potent and biostable insect kinin mimics. On the Ae. aegypti mosquito kinin receptor, three highly potent, biostable Aib analogs matched the activity of the Aib-containing biostable insect kinin analog 1728, which previously showed disruptive and/or aversive activity in aphid, mosquito and kissing bug. These three analogs are IK-Aib-19 ([Aib]FY[Aib]WGa, EC50 = 18 nM), IK-Aib-12 (pQKFY[Aib]WGa, EC50 = 23 nM) and IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 28 nM). On the Rhipicephalus (Boophilus) microplus tick receptor, IK-Aib-20 ([Aib]FH[Aib]WGa, EC50 = 2 nM) is more potent than 1728 by a factor of 3. Seven other potentially biostable analogs exhibited an EC50 range of 5-10 nM, all of which match the potency of 1728. Among the multi-Aib hexapeptide kinin analogs tested the tick receptor has a preference for the positively-charged, aromatic H over the aromatic residues Y and F in the X1 variable position ([Aib]FX1[Aib]WGa), whereas the mosquito receptor does not distinguish between them. In contrast, in a mono-Aib pentapeptide analog framework (FX1[Aib]WGa), both receptors exhibit a preference for Y over H in the variable position. Among analogs incorporating polyethylene glycol (PEG) polymer attachments at the N-terminus that can confer enhanced bioavailability and biostability, three matched or surpassed the potency of a positive control peptide. On the tick receptor IK-PEG-9 (P8-R[Aib]FF[Aib]WGa) was the most potent. Two others, IK-PEG-8 (P8-RFFPWGa) and IK-PEG-6 (P4-RFFPWGa), were most potent on the mosquito receptor, with the first surpassing the activity of the positive control peptide. These analogs and others in the IK-Aib series expand the toolbox of potent analogs accessible to invertebrate endocrinologists studying the structural requirements for bioactivity and the as yet unknown role of the insect kinins in ticks. They may contribute to the development of selective, environmentally friendly pest arthropod control agents.


Assuntos
Aedes/efeitos dos fármacos , Ácidos Aminoisobutíricos/química , Cininas/farmacologia , Controle de Pragas , Polietilenoglicóis/química , Receptores Acoplados a Proteínas G/metabolismo , Rhipicephalus/efeitos dos fármacos , Aedes/metabolismo , Sequência de Aminoácidos , Animais , Disponibilidade Biológica , Cininas/química , Rhipicephalus/metabolismo , Relação Estrutura-Atividade
10.
Chemistry ; 25(9): 2288-2294, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30421558

RESUMO

The simplest non-proteinogenic amino acid α-aminoisobutyric acid (Aib), an analogue of glycine and alanine, has been vaporized by laser ablation and probed by high-resolution Fourier transform microwave spectroscopic techniques. Comparison of the experimental rotational and 14 N nuclear quadrupole constants with that predicted ab initio has allowed the identification of three conformers of Aib exhibiting three types of hydrogen-bond interactions I (NH⋅⋅⋅O=C, cis-COOH), II (OH⋅⋅⋅N, trans-COOH), and III (N-H⋅⋅⋅O-H, cis-COOH) within the amino acid backbone. The observation of conformer III, not detected previously for related proteinogenic amino acids with a nonpolar side chain in a supersonic expansion, indicates that the presence of the methyl groups should restrict the conformational relaxation from conformer Aib-III to Aib-I. For conformer Aib-II, the rotational spectra of the 13 C isotopomers reveal a tunneling motion arising from the two equivalent methyl groups in the molecule. The observation of a single spectrum at the midpoint between those predicted for the two 13 C of the methyl groups has been explained by considering a double-minimum potential function with a low-energy interconversion barrier for a large amplitude internal motion. This singular fact has been corroborated by the anomalous centrifugal distortion effects determined in conformer Aib-II.


Assuntos
Ácidos Aminoisobutíricos , Alanina/análogos & derivados , Ácidos Aminoisobutíricos/química , Glicina/análogos & derivados , Ligação de Hidrogênio , Conformação Molecular
11.
J Phys Chem B ; 122(24): 6305-6313, 2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29792795

RESUMO

Peptide self-assembly is ubiquitous in nature. It governs the organization of proteins, controlling their folding kinetics and preserving their structural stability and bioactivity. In this connection, model oligopeptides may give important insights into the molecular mechanisms and elementary forces driving the formation of supramolecular structures. In this contribution, we show that a single residue substitution, that is, Aib (α-aminoisobutyric acid) in place of Ala at position 4 of an -(l-Ala)5-homo-oligomer, strongly alters the aggregation process. In particular, this process is initiated by the formation of small peptide clusters that promote aggregation on the nanometer scale and, through a hierarchical self-assembly, lead to mesoscopic structures of micrometric dimensions. Furthermore, we show that the use of the well-established Langmuir-Blodgett technique represents an effective strategy for coating extended areas of inorganic substrates by densely packed peptide layers, thus paving the way for application of peptide films as templates for biomineralization, biocompatible coating of surfaces, and scaffolds for tissue engineering.


Assuntos
Nanoestruturas/química , Oligopeptídeos/química , Ar , Ácidos Aminoisobutíricos/química , Microscopia de Força Atômica , Simulação de Dinâmica Molecular , Oligopeptídeos/metabolismo , Estrutura Secundária de Proteína , Espectrometria de Fluorescência , Água/química
12.
Phys Chem Chem Phys ; 20(22): 15216-15222, 2018 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-29789853

RESUMO

Electron transfer (ET) reactions via helical peptides composed of -(Aib-Pro)n- were studied in self-assembled monolayers and compared with -(Ala-Aib)n- peptides. Short Aib-Pro peptides showed slightly higher ET rates due to the better electronic coupling of the Pro residue. But, the 24mer Aib-Pro peptide showed a smaller ET rate than the corresponding Ala-Aib peptide. On the basis of DFT calculations, the deceleration of the ET rate of the longer Aib-Pro peptide is considered to be due to the smaller number of active modes of accordion-like oscillations than the Ala-Aib peptide, which has a strong influence on a long-range ET reaction.


Assuntos
Peptídeos/química , Sequência de Aminoácidos , Ácidos Aminoisobutíricos/química , Transporte de Elétrons , Ouro/química , Cinética , Modelos Moleculares , Prolina/análogos & derivados , Prolina/química , Multimerização Proteica , Estrutura Secundária de Proteína , Teoria Quântica
13.
Chemistry ; 24(37): 9399-9408, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29745985

RESUMO

Helical α-aminoisobutyric acid (Aib) foldamers show great potential as devices for the communication of conformational information across phospholipid bilayers, but determining their conformation in bilayers remains a challenge. In the present study, Raman, Raman optical activity (ROA), infrared (IR) and vibrational circular dichroism (VCD) spectroscopies have been used to analyze the conformational preferences of Aib foldamers in solution and when interacting with bilayers. A 310 -helix marker band at 1665-1668 cm-1 in Raman spectra was used to show that net helical content increased strongly with oligomer length. ROA and VCD spectra of chiral Aib foldamers provided the chiroptical signature for both left- and right-handed 310 -helices in organic solvents, with VCD establishing that foldamer screw-sense was preserved when the foldamers became embedded within bilayers. However, the population distribution between different secondary structures was perturbed by the chiral phospholipid. These studies indicate that ROA and VCD spectroscopies are valuable tools for the study of biomimetic structures, such as artificial signal transduction molecules, in phospholipid bilayers.


Assuntos
Ácidos Aminoisobutíricos/química , Dicroísmo Circular/métodos , Bicamadas Lipídicas/química , Fosfolipídeos/química , Solventes/química , Espectrofotometria Infravermelho/métodos , Modelos Moleculares , Conformação Molecular , Estrutura Secundária de Proteína , Análise Espectral Raman/métodos , Estereoisomerismo
14.
Arch Pharm Res ; 41(5): 481-489, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29696569

RESUMO

4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4-dimethyloxazolone via an intramolecular cyclization. We discovered that the 4,4-dimethyloxazolone of an AIB urethane is in fact an excellent electrophile that enables efficient amidation even with weakly reactive nucleophiles. The 4,4-dimethyloxazolone can be stored in a pure form and used as a reagent offering an efficient and convenient synthetic tool for generating AIB-peptide analogs.


Assuntos
Amidas/química , Ácidos Aminoisobutíricos/síntese química , Oxazolona/química , Ácidos Aminoisobutíricos/química , Estrutura Molecular
15.
Peptides ; 102: 54-60, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29475074

RESUMO

The peptides orexin-A and -B, the endogenous agonists of the orexin receptors, have similar 19-amino-acid C-termini which retain full maximum response as truncated peptides with only marginally reduced potency, while further N-terminal truncations successively reduce the activity. The peptides have been suggested to bind in an α-helical conformation, and truncation beyond a certain critical length is likely to disrupt the overall helical structure. In this study, we set out to stabilize the α-helical conformation of orexin-A15-33 via peptide stapling at four different sites. At a suggested hinge region, we varied the length of the cross-linker as well as replaced the staple with two α-aminoisobutyric acid residues. Modifications close to the peptide C-terminus, which is crucial for activity, were not allowed. However, central and N-terminal modifications yielded bioactive peptides, albeit with decreased potencies. This provides evidence that the orexin receptors can accommodate and be activated by α-helical peptides. The decrease in potency is likely linked to a stabilization of suboptimal peptide conformation or blocking of peptide backbone-receptor interactions at the hinge region by the helical stabilization or the modified amino acids.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/química , Receptores de Orexina/química , Orexinas/química , Peptídeos/química , Sequência de Aminoácidos , Ácidos Aminoisobutíricos/química , Humanos , Receptores de Orexina/agonistas , Peptídeos/metabolismo , Conformação Proteica em alfa-Hélice
16.
J Nat Prod ; 81(2): 219-226, 2018 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-29373791

RESUMO

Four novel lipovelutibols A (1), B (2), C (3), and D (4) containing six amino acid residues with leucinol at the C-terminus and a fatty acyl moiety (n-octanoyl) at its N-terminus were isolated from the psychrotrophic fungus Trichoderma velutinum collected from the Himalayan cold habitat. The structures (1-4) were determined by NMR and MS/MS, and the stereochemistry of amino acids by Marfey's method. Lipopeptaibols 2 and 4 were found to contain d-isovaline, a nonproteinogenic amino acid, but lacked α-aminoisobutyric acid, characteristic of peptaibols. Cytotoxic activity of 2 and 4 was observed against HL-60, LS180, MDA-MB-231, and A549 cancer cell lines.


Assuntos
Peptaibols/química , Trichoderma/química , Células A549 , Aminoácidos/química , Ácidos Aminoisobutíricos/química , Linhagem Celular Tumoral , Temperatura Baixa , Ecossistema , Células HL-60 , Humanos , Leucina/análogos & derivados , Leucina/química , Espectroscopia de Ressonância Magnética/métodos , Peptaibols/farmacologia , Espectrometria de Massas em Tandem/métodos , Valina/química
17.
Chemistry ; 24(9): 2249-2256, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29210477

RESUMO

Peptaibols are peptide antibiotics that typically feature an N-terminal acetyl cap, a C-terminal aminoalcohol, and a high proportion of α-aminoisobutyric acid (Aib) residues. To establish how each feature might affect the membrane-activity of peptaibols, biomimetic Aib foldamers with different lengths and terminal groups were synthesised. Vesicle assays showed that long foldamers (eleven Aib residues) with hydrophobic termini had the highest ionophoric activity. C-terminal acids or primary amides inhibited activity, while replacement of an N-terminal acetyl with an azide group made little difference. Crystallography showed that N3 Aib11 CH2 OTIPS folded into a 310 helix 2.91 nm long, which is close to the bilayer hydrophobic width. Planar bilayer conductance assays showed discrete ion channels only for N-acetylated foldamers. However long foldamers with hydrophobic termini had the highest antibacterial activity, indicating that ionophoric activity in vesicles was a better indicator of antibacterial activity than the observation of discrete ion channels.


Assuntos
Ácidos Aminoisobutíricos/química , Antibacterianos/química , Bicamadas Lipídicas/metabolismo , Peptaibols/metabolismo , Alameticina/farmacologia , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Cristalografia por Raios X , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Interações Hidrofóbicas e Hidrofílicas , Bicamadas Lipídicas/química , Lipossomos/química , Lipossomos/metabolismo , Conformação Molecular , Peptaibols/química
18.
Bioorg Med Chem Lett ; 27(24): 5378-5381, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29157863

RESUMO

The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure-activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells.


Assuntos
Ácidos Aminoisobutíricos/química , Portadores de Fármacos/química , Oligopeptídeos/química , Peptídeos Cíclicos/química , RNA Interferente Pequeno/metabolismo , Células A549 , Sequência de Aminoácidos , Dicroísmo Circular , Corantes Fluorescentes/química , Fluorbenzenos/química , Humanos , Microscopia de Fluorescência , Interferência de RNA , RNA Interferente Pequeno/química , Relação Estrutura-Atividade , Transfecção/métodos
19.
Chem Commun (Camb) ; 53(53): 7318-7321, 2017 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-28485427

RESUMO

Polypeptides containing 2-aminoisobutyric acid (Aib) units as an unnatural amino acid residue were synthesized by papain-catalyzed chemoenzymatic polymerization of a tripeptide ethyl ester l-Ala-Aib-l-Ala-OEt in an aqueous medium. The Aib-containing polypeptide adopted an α-helix conformation in both the solid and solution phases, which was induced by the periodic Aib residue.


Assuntos
Ácidos Aminoisobutíricos/metabolismo , Papaína/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Ácidos Aminoisobutíricos/química , Biocatálise , Estrutura Molecular , Peptídeos/química
20.
J Pept Sci ; 23(2): 104-116, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28054413

RESUMO

The role of the conformationally constrained α-aminoisobutyric acid (Aib) residue in the aggregation and self-assembly properties of oligopeptides is discussed, critically reviewing our recent work in the field. In this connection, three significant case studies are presented: (i) aggregation propensity of Aib homo-oligopeptides of different length; (ii) perturbation of the conformational and aggregation properties of Ala-based pentapeptides by a single Aib versus Ala substitution; and (iii) build up of self-assembled monolayers formed by Aib homo-hexapeptide building blocks. The peptides investigated were all functionalized by a fluorescent probe, that is, a naphthyl group in the first case-study and a pyrenyl group in the other two, with the aim at applying optical spectroscopy techniques and evaluating the relevance of aromatic interactions in the aggregation process. Microscopy techniques at nanometric resolution and results of molecular dynamics simulations are also presented to analyze how the conformational properties of the peptide building blocks would affect the morphology of the peptide aggregates from the nanoscale to the mesoscale. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.


Assuntos
Ácidos Aminoisobutíricos/química , Oligopeptídeos/química , Agregados Proteicos , Sequência de Aminoácidos , Corantes Fluorescentes/química , Ligação de Hidrogênio , Microscopia de Força Atômica , Simulação de Dinâmica Molecular , Sondas Moleculares/química , Estrutura Secundária de Proteína , Soluções , Espectrometria de Fluorescência
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