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1.
J Am Chem Soc ; 146(9): 6369-6376, 2024 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-38377472

RESUMO

Systematic structural studies of model oligopeptides revealed important aspects of protein folding and offered design principles to access non-natural materials. In the same way, the rules that regulate glycan folding could be established by studying synthetic oligosaccharide models. However, their analysis is often limited due to the synthetic and analytical complexity. By utilizing a glycan capable of spontaneously folding into a hairpin conformation as a model system, we investigated the factors that contribute to its conformational stability in aqueous solution. The modular design of the hairpin model featured a trisaccharide turn unit and two ß-1,4-oligoglucoside stacking strands that allowed for systematic chemical modifications of the glycan sequence, including the introduction of NMR labels and staples. Nuclear magnetic resonance assisted by molecular dynamics simulations revealed that stereoelectronic effects and multiple glycan-glycan interactions are the major determinants of folding stabilization. Chemical modifications in the glycan primary sequence (e.g., strand elongation) can be employed to fine-tune the rigidity of structural motifs distant from the modification sites. These results could inspire the design of other glycan architectures, with implications in glycobiology and material sciences.


Assuntos
Oligopeptídeos , Dobramento de Proteína , Sequência de Aminoácidos , Conformação Molecular , Oligopeptídeos/química , Polissacarídeos
2.
Chemistry ; 30(42): e202401943, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38771268

RESUMO

Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e. g., by using small tertiary amide N-substituents (Me, Et, Pr) on the tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e. g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.


Assuntos
Antineoplásicos , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Imunoconjugados/química , Compostos de Amônio Quaternário/química , Oligopeptídeos/química , Linhagem Celular Tumoral
3.
Chemistry ; 29(54): e202301678, 2023 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-37358020

RESUMO

Biomaterials with improved biological features can be obtained by conjugating glycans to nanostructured peptides. Creating peptide-glycan chimeras requires superb chemoselectivity. We expedite access to such chimeras by merging peptide and glycan solid-phase syntheses employing a bifunctional monosaccharide. The concept was explored in the context of the on-resin generation of a model α(1→6)tetramannoside linked to peptides, lipids, steroids, and adamantane. Chimeras containing a ß(1→6)tetraglucoside and self-assembling peptides such as FF, FFKLVFF, and the amphiphile palmitoyl-VVVAAAKKK were prepared in a fully automated manner. The robust synthetic protocol requires a single purification step to obtain overall yields of about 20 %. The ß(1→6)tetraglucoside FFKLVFF chimera produces micelles rather than nanofibers formed by the peptide alone as judged by microscopy and circular dichroism. The peptide amphiphile-glycan chimera forms a disperse fiber network, creating opportunities for new glycan-based nanomaterials.

4.
Beilstein J Org Chem ; 19: 1015-1020, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37440787

RESUMO

Automated glycan assembly (AGA) affords collections of well-defined glycans in a short amount of time. We systematically analyzed how parameters connected to the solid support affect the AGA outcome for three different glycan sequences. We showed that, while loading and reaction scale did not significantly influence the AGA outcome, the chemical nature of the linker dramatically altered the isolated yields. We identified that the major determinants of AGA yields are cleavage from the solid support and post-AGA purification steps.

5.
J Am Chem Soc ; 144(40): 18429-18434, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36173281

RESUMO

Stapling short peptides to lock specific conformations and thereby obtain superior pharmacological properties is well established. However, similar concepts have not been applied to oligosaccharides. Here, we describe the design, synthesis, and characterization of the first stapled oligosaccharides. Automated assembly of ß-(1,6)-glucans equipped with two alkenyl side chains was followed by on-resin Grubbs metathesis for efficient ring closure with a variety of cross-linkers of different sizes. Oligosaccharide stapling increases enzymatic stability and cell penetration, therefore opening new opportunities for the use of glycans in medicinal chemistry.


Assuntos
Oligossacarídeos , Peptídeos , Glucanos/química , Conformação Molecular , Oligossacarídeos/química , Peptídeos/química , Polissacarídeos
6.
Chemistry ; 27(47): 12032-12035, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34081364

RESUMO

Aetokthonotoxin has recently been identified as the cyanobacterial neurotoxin causing Vacuolar Myelinopathy, a fatal neurologic disease, spreading through a trophic cascade and affecting birds of prey such as the bald eagle in the USA. Here, we describe the total synthesis of this specialized metabolite. The complex, highly brominated 1,2'-biindole could be synthesized via a Somei-type Michael reaction as key step. The optimised sequence yielded the natural product in five steps with an overall yield of 29 %.


Assuntos
Doenças das Aves , Doenças do Sistema Nervoso Central , Águias , Animais , Bainha de Mielina , Neurotoxinas/toxicidade
7.
Bioorg Chem ; 113: 104987, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34022444

RESUMO

The stabilization of helical structures by peptide stapling approaches is now a mature technology capable to provide a variety of biomedical applications. Recently, it was shown that multicomponent macrocyclization is not only an effective way to introduce conformational constraints but it also allows to incorporate additional functionalities to the staple moiety in a one-pot process. This work investigates the scope of the double Ugi multicomponent stapling approach in its capacity to produce helical peptides from unstructured sequences. For this, three different stapling combinations were implemented and the CD spectra of the cyclic peptides were measured to determine the effect of the multicomponent macrocyclization on the resulting secondary structure. A new insight into some structural factors influencing the helicity type and content is provided, along with new prospects on the utilization of this methodology to diversify the molecular tethers linking the amino acid side chains.


Assuntos
Peptídeos/síntese química , Dicroísmo Circular , Peptídeos/química , Conformação Proteica em alfa-Hélice
8.
Int J Mol Sci ; 22(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34884518

RESUMO

Fungal species of genus Sepedonium are rich sources of diverse secondary metabolites (e.g., alkaloids, peptaibols), which exhibit variable biological activities. Herein, two new peptaibols, named ampullosporin F (1) and ampullosporin G (2), together with five known compounds, ampullosporin A (3), peptaibolin (4), chrysosporide (5), c(Trp-Ser) (6) and c(Trp-Ala) (7), have been isolated from the culture of Sepedonium ampullosporum Damon strain KSH534. The structures of 1 and 2 were elucidated based on ESI-HRMSn experiments and intense 1D and 2D NMR analyses. The sequence of ampullosporin F (1) was determined to be Ac-Trp1-Ala2-Aib3-Aib4-Leu5-Aib6-Gln7-Aib8-Aib9-Aib10-GluOMe11-Leu12-Aib13-Gln14-Leuol15, while ampullosporin G (2) differs from 1 by exchanging the position of Gln7 with GluOMe11. Furthermore, the total synthesis of 1 and 2 was carried out on solid-phase to confirm the absolute configuration of all chiral amino acids as L. In addition, ampullosporin F (1) and G (2) showed significant antifungal activity against B. cinerea and P. infestans, but were inactive against S. tritici. Cell viability assays using human prostate (PC-3) and colorectal (HT-29) cancer cells confirmed potent anticancer activities of 1 and 2. Furthermore, a molecular docking study was performed in silico as an attempt to explain the structure-activity correlation of the characteristic ampullosporins (1-3).


Assuntos
Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Ésteres/química , Ácido Glutâmico/química , Hypocreales/fisiologia , Neoplasias/tratamento farmacológico , Peptaibols/farmacologia , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Humanos , Neoplasias/patologia , Peptaibols/química , Phytophthora infestans/efeitos dos fármacos , Células Tumorais Cultivadas
9.
Angew Chem Int Ed Engl ; 59(1): 259-263, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31797518

RESUMO

In contrast to the myriad of methods available to produce α-helices and antiparallel ß-sheets in synthetic peptides, just a few are known for the construction of stable, non-cyclic parallel ß-sheets. Herein, we report an efficient on-resin approach for the assembly of parallel ß-sheet peptides in which the N-alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N-alkylated turn using the Ugi reaction on varied isocyano-resins. This four-component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better-structured and more stable parallel ß-sheets in the N-alkylated peptides compared to the non-functionalized variants.

10.
Angew Chem Int Ed Engl ; 59(13): 5235-5241, 2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31944488

RESUMO

Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of α-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo- and endo-cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography.


Assuntos
Peptídeos/química , Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/química , Proteína Supressora de Tumor p53/química , Aldeídos/química , Aminas/química , Sequência de Aminoácidos , Domínio Catalítico , Cristalografia por Raios X , Cianetos/química , Polarização de Fluorescência , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Ligação Proteica , Conformação Proteica
11.
Chemistry ; 25(3): 769-774, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30412333

RESUMO

The multicomponent backbone N-modification of peptides on solid-phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N-substituents suitable for backbone stapling can be readily introduced by means of on-resin Ugi multicomponent reactions conducted during solid-phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N-substituents, including the ring-closing metathesis, lactamization, and thiol alkylation. The backbone N-modification method was also applied to the synthesis of α-helical peptides by linking N-substituents to the peptide N-terminus, thus featuring hydrogen-bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.


Assuntos
Amidas/química , Peptídeos/química , Alquilação , Ciclização , Ligação de Hidrogênio , Nitrogênio/química , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Estrutura Secundária de Proteína , Técnicas de Síntese em Fase Sólida , Compostos de Sulfidrila/química
12.
Angew Chem Int Ed Engl ; 58(9): 2700-2704, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30589179

RESUMO

For the first time, the Petasis (borono-Mannich) reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid-phase derivatization of peptides at the N-terminus, Lys, and Nϵ -MeLys side-chains by an on-resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid, and aldoses, thus encompassing a powerful complexity-generating approach without changing the charge of the peptides. The multicomponent stapling was conducted in solution by linking Nϵ -MeLys or Orn side-chains, positioned at i, i+7 and i, i+4, with aryl tethers, while hydroxy carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology.

13.
Org Biomol Chem ; 13(2): 438-46, 2015 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-25371987

RESUMO

Increasing the diversity of peptide cyclization methods is an effective way of accessing new types of macrocyclic chemotypes featuring a wide variety of ring sizes and topologies. Multicomponent reactions (MCRs) are processes capable of generating great levels of molecular diversity and complexity at low synthetic cost. In an attempt to further exploit MCRs in the field of cyclopeptides, we describe a bidirectional multicomponent approach for the synthesis of N-alkylated macrocyclic peptides of varied sequences and cross-linking positions. The process relies on the execution of two Ugi reactions between peptide diacids and diisocyanides. Varying the amino component enabled the installation of exocyclic elements of diversity, while skeletal diversity was created through different side chain and backbone cyclizations. This procedure shows prospects for the rapid scanning of the chemical space of macrocyclic peptides for applications in chemical biology and drug discovery.


Assuntos
Compostos Macrocíclicos/química , Peptídeos Cíclicos/química , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
14.
Methods Mol Biol ; 2371: 143-157, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34596847

RESUMO

Multicomponent reactions (MCRs) are recently expanding the plethora of solid-phase protocols for the synthesis and derivatization of peptides. Herein, we describe a solid-phase-compatible strategy based on MCRs as a powerful strategy for peptide cyclization and ligation . We illustrate, using Gramicidin S as a model peptide, how the execution of on-resin Ugi reactions enables the simultaneous backbone N-functionalization and cyclization, which are important types of derivatizations in peptide-based drug development or for incorporation of conjugation handles, or labels.


Assuntos
Peptídeos Cíclicos/química , Ciclização , Gramicidina
15.
Nat Protoc ; 16(2): 561-578, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33473197

RESUMO

Solid-phase synthesis represents the methodological showcase for technological advances such as split-and-pool combinatorial chemistry and the automated synthesis of peptides, nucleic acids and polysaccharides. These strategies involve iterative coupling cycles that do not generate functional diversity besides that incorporated by the amino acids, nucleosides and monosaccharide building blocks. In sharp contrast, multicomponent reactions (MCRs) are traditionally used to generate both skeletal and appendage diversity in short, batchwise procedures. On-resin MCRs have traditionally been employed for the construction of heterocycle and peptidomimetic libraries, but that scenario has changed recently, and today the focus is more on the solid-phase derivatization of peptides and oligonucleotides. This review presents relevant experimental details and addresses the synthetic scope of such on-resin multicomponent protocols employed to accomplish specific biopolymer covalent modifications that are practically inviable by traditional solution-phase methodologies. Recommendations are provided to facilitate the implementation of solid-supported protocols and avoid possible pitfalls associated with the selection of the polymeric resin, the solvent and the order and amount of the reagents employed. We describe procedures comprising the multicomponent lipidation, biotinylation and labeling of both termini and the side chains, as well as the use of MCRs in the traceless on-resin synthesis of ligated and cyclic peptides. Solid-phase protocols for the assembly of α-helical and parallel ß-sheet peptides as well as hybrid peptide-peptoid and peptide-peptide nucleic acid architectures are described. Finally, the solid-supported multicomponent derivatization of DNA oligonucleotides is illustrated as part of the DNA-encoded library technology relying on MCR-derived heterocyclic compounds.


Assuntos
Biopolímeros/química , Técnicas de Química Combinatória/métodos , Técnicas de Síntese em Fase Sólida/métodos , Aminas , Aminoácidos , Biopolímeros/biossíntese , Biotinilação , DNA , Compostos Heterocíclicos , Oligonucleotídeos , Peptídeos/síntese química , Peptídeos Cíclicos , Resinas Sintéticas/química
16.
ACS Chem Biol ; 16(7): 1223-1233, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34219448

RESUMO

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to elicit neutralizing antibodies to block viral sites binding to the host's cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of immunization and correlates well with viral neutralization. Here, we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid (TT) induce a potent immune response in laboratory animals. Some advantages of immunization with RBD-TT conjugates include a predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. These result demonstrate the potential of the conjugate COVID-19 vaccine candidates and enable their advance to clinical evaluation under the name SOBERANA02, paving the way for other antiviral conjugate vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Toxoide Tetânico/química , Vacinas Conjugadas/administração & dosagem , Animais , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vacinação , Vacinas Conjugadas/imunologia
17.
Org Lett ; 21(18): 7307-7310, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31482710

RESUMO

A solid-phase approach including on-resin Ugi reactions was developed for the construction of ß-hairpins. Various N-alkylated dipeptide fragments proved capable of aligning antiparallel ß-sheets in a macrocyclic scaffold, thus serving as ß-hairpin templates. Gramicidin S was used as the model ß-hairpin to compare the Ugi-derived ß-turns with the type-II' ß-turn. The results show that the multicomponent incorporation of such N-alkylated residues allows for the simultaneous stabilization and exo-cyclic functionalization of cyclic ß-hairpins.


Assuntos
Dipeptídeos/química , Gramicidina/síntese química , Alquilação , Dipeptídeos/síntese química , Gramicidina/química , Conformação Molecular , Estabilidade Proteica , Estrutura Secundária de Proteína , Técnicas de Síntese em Fase Sólida
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