RESUMO
Oligonucleotides carrying 3'-terminal phosphates and conjugates are important tools in molecular biology and diagnostic purposes. We described the preparation of solid supports carrying the base labile linker 4-((2-hydroxyethyl)sulfonyl)benzamide for the solid-phase synthesis of 3'-phosphorylated oligonucleotides. These supports are fully compatible with the phosphoramidite chemistry yielding the desired 3'-phosphate oligonucleotides in excellent yields. The use of mild deprotection conditions allows the generation of partially protected DNA fragments.
Assuntos
Oligonucleotídeos , Técnicas de Síntese em Fase Sólida , Oligonucleotídeos/química , Oligonucleotídeos/síntese química , Fosfatos/química , Benzamidas/química , Benzamidas/síntese química , Compostos Organofosforados/química , Compostos Organofosforados/síntese química , Fosforilação , Estrutura MolecularRESUMO
Since the last century, peptides have gained wide acceptance as drugs, with almost 100 already in the market and a large number in the pipeline. In this context, peptide synthesis has grown massively as a stringent field for pharmaceuticals around the globe. Three methodologies, namely, classical solution peptide synthesis (CSPS), solid-phase peptide synthesis (SPPS), and liquid-phase peptide synthesis (LPPS), have made significant contributions to the field. This review provides a comprehensive and integrated vision of LPPS as the third wave for peptide synthesis. LPPS combines the advantages of CSPS and SPPS, where peptide elongation is carried out in solution and the growing peptide chain is supported on a soluble tag, which confers characteristic properties. LPPS protocols allow the large-scale production of peptides and reduce the use of excess reagents and solvents, thus meeting the principles of green chemistry. In this review, tags associated with LPPS are broadly discussed under the following headings: polydisperse polyethylene glycol (PEG), membrane-enhanced peptide synthesis (MEPS), fluorous technology, ionic liquids (ILs), PolyCarbon, hydrophobic polymers, and group-assisted purification (GAP). It also highlights the signature accomplishments of LPPS tags and the limitations of the same.
Assuntos
Líquidos Iônicos , Peptídeos , Técnicas de Química Sintética , Peptídeos/química , Solventes/químicaRESUMO
Morpholine, which scores 7.5 in terms of greenness and is not a regulated substance, could be considered a strong contender for Fmoc removal in solid-phase peptide synthesis (SPPS). Morpholine in dimethylformamide (DMF) (50%-60%) efficiently removes Fmoc in SPPS, minimizes the formation of diketopiperazine, and almost avoids the aspartimide formation. As a proof of concept, somatostatin has been synthesized using 50% morpholine in DMF with the same purity as when using 20% piperidine-DMF.
Assuntos
Fluorenos , Técnicas de Síntese em Fase Sólida , Fluorenos/química , MorfolinasRESUMO
The adaptation of amphibians to diverse environments is closely related to the characteristics of their skin. The complex glandular system of frog skin plays a pivotal role in enabling these animals to thrive in both aquatic and terrestrial habitats and consists of crucial functions such as respiration and water balance as well as serving as a defensive barrier due to the secretion of bioactive compounds. We herein report the first investigation on the skin secretion of Odontophrynus americanus, as a potential source of bioactive peptides and also as an indicator of its evolutionary adaptations to changing environments. Americanin-1 was isolated and identified as a neutral peptide exhibiting moderate antibacterial activity against E. coli. Its amphipathic sequence including 19 amino acids and showing a propensity for α-helix structure is discussed. Comparisons of the histomorphology of the skin of O. americanus with other previously documented species within the same genus revealed distinctive features in the Patagonian specimen, differing from conspecifics from other Argentine provinces. The presence of the Eberth-Katschenko layer, a prevalence of iridophores, and the existence of glycoconjugates in its serous glands suggest that the integument is adapted to retain skin moisture. This adaptation is consistent with the prevailing aridity of its native habitat.
Assuntos
Anuros , Pele , Animais , Pele/química , Escherichia coli/efeitos dos fármacos , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Estrutura Molecular , Argentina , Peptídeos/química , Peptídeos/farmacologia , Sequência de Aminoácidos , Testes de Sensibilidade MicrobianaRESUMO
This research presents the development of positron emission tomography (PET) radiotracers for detecting Mycobacterium tuberculosis (MTB) for the diagnosis and monitoring of tuberculosis. Two phage display-derived peptides with proven selective binding to MTB were identified for development into PET radiopharmaceuticals: H8 (linear peptide) and PH1 (cyclic peptide). We sought to functionalize H8/PH1 with NODASA, a bifunctional chelator that allows complexation of PET-compatible radiometals such as gallium-68. Herein, we report on the chelator functionalization, optimized radiosynthesis, and assessment of the radiopharmaceutical properties of [68Ga]Ga-NODASA-H8 and [68Ga]Ga-NODASA-PH1. Robust radiolabeling was achieved using the established routine method, indicating consistent production of a radiochemically pure product (RCP ≥ 99.6%). For respective [68Ga]Ga-NODASA-H8 and [68Ga]Ga-NODASA-PH1, relatively high levels of decay-corrected radiochemical yield (91.2% ± 2.3%, 86.7% ± 4.0%) and apparent molar activity (Am, 3.9 ± 0.8 and 34.0 ± 5.3 GBq/µmol) were reliably achieved within 42 min, suitable for imaging purposes. Notably, [68Ga]Ga-NODASA-PH1 remained stable in blood plasma for up to 2 h, while [68Ga]Ga-NODASA-H8 degraded within 30 min. For both 68Ga peptides, minimal whole-blood cell binding and plasma protein binding were observed, indicating a favorable pharmaceutical behavior. [68Ga]Ga-NODASA-PH1 is a promising candidate for further in vitro/in vivo evaluation as a tuberculosis-specific infection imaging agent.
RESUMO
Peptide nucleic acids (PNAs) are an important class of DNA/RNA mimics that can hybridize complementary chains of nucleic acids with high affinity and specificity. Because of this property and their metabolic stability, PNAs have broad potential applications in different fields. Consisting of a neutral polyamide backbone, PNAs are prepared following the method used for peptide synthesis. In this regard, they are prepared by the sequential coupling of the protected monomers on a solid support using a similar approach to solid-phase peptide synthesis (SPPS). However, PNA synthesis is a little more challenging due to issues of the difficulty on the preparation of monomers and their solubility. Furthermore, the PNA elongation is jeopardized by intra/inter chain aggregation and side reactions. These hurdles can be overcome using different protecting group strategies on the PNA monomer, which also dictate the approach followed to prepare the oligomers. Herein, the main synthetic strategies driven by the protecting group scheme are discussed. However, there is still ample scope for further enhancement of the overall process.
Assuntos
Ácidos Nucleicos , Ácidos Nucleicos Peptídicos , Ácidos Nucleicos Peptídicos/química , DNA/química , Peptídeos , RNA/químicaRESUMO
Peptides displaying antimicrobial properties are being regarded as useful tools to evade and combat antimicrobial resistance, a major public health challenge. Here we have addressed dendrimers, attractive molecules in pharmaceutical innovation and development displaying broad biological activity. Triazine-based dendrimers were fully synthesized in the solid phase, and their antimicrobial activity and some insights into their mechanisms of action were explored. Triazine is present in a large number of compounds with highly diverse biological targets with broad biological activities and could be an excellent branching unit to accommodate peptides. Our results show that the novel peptide dendrimers synthesized have remarkable antimicrobial activity against Gram-negative bacteria (E. coli and P. aeruginosa) and suggest that they may be useful in neutralizing the effect of efflux machinery on resistance.
Assuntos
Dendrímeros , Escherichia coli , Testes de Sensibilidade Microbiana , Triazinas , Dendrímeros/química , Dendrímeros/síntese química , Dendrímeros/farmacologia , Triazinas/química , Triazinas/farmacologia , Triazinas/síntese química , Escherichia coli/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/síntese química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/síntese químicaRESUMO
Solid-phase peptide synthesis (SPPS) is the preferred strategy for synthesizing most peptides for research purposes and on a multi-kilogram scale. One key to the success of SPPS is the continual evolution and improvement of the original method proposed by Merrifield. Over the years, this approach has been enhanced with the introduction of new solid supports, protecting groups for amino acids, coupling reagents, and other tools. One of these improvements is the use of the so-called "safety-catch" linkers/resins. The linker is understood as the moiety that links the peptide to the solid support and protects the C-terminal carboxylic group. The "safety-catch" concept relies on linkers that are totally stable under the conditions needed for both α-amino and side-chain deprotection that, at the end of synthesis, can be made labile to one of those conditions by a simple chemical reaction (e.g., an alkylation). This unique characteristic enables the simultaneous use of two primary protecting strategies: tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). Ultimately, at the end of synthesis, either acids (which are incompatible with Boc) or bases (which are incompatible with Fmoc) can be employed to cleave the peptide from the resin. This review focuses on the most significant "safety-catch" linkers.
Assuntos
Antifibrinolíticos , Técnicas de Síntese em Fase Sólida , Alquilação , Aminoácidos , Resinas Vegetais , PeptídeosRESUMO
With the COVID-19 pandemic behind us, the U.S. Food and Drug Administration (FDA) has approved 55 new drugs in 2023, a figure consistent with the number authorized in the last five years (53 per year on average). Thus, 2023 marks the second-best yearly FDA harvest after 2018 (59 approvals) in all the series. Monoclonal antibodies (mAbs) continue to be the class of drugs with the most approvals, with an exceptional 12, a number that makes it the most outstanding year for this class. As in 2022, five proteins/enzymes have been approved in 2023. However, no antibody-drug conjugates (ADCs) have been released onto the market. With respect to TIDES (peptides and oligonucleotides), 2023 has proved a spectacular year, with a total of nine approvals, corresponding to five peptides and four oligonucleotides. Natural products continue to be the best source of inspiration for drug development, with 10 new products on the market. Three drugs in this year's harvest are pegylated, which may indicate the return of pegylation as a method to increase the half-lives of drugs after the withdrawal of peginesatide from the market in 2013. Following the trends in recent years, two bispecific drugs have been authorized in 2023. As in the preceding years, fluorine and/or N-aromatic heterocycles are present in most of the drugs. Herein, the 55 new drugs approved by the FDA in 2023 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins/enzymes); TIDES (peptide and oligonucleotides); combined drugs; pegylated drugs; natural products; nitrogen aromatic heterocycles; fluorine-containing molecules; and other small molecules.
Assuntos
Produtos Biológicos , Aprovação de Drogas , Estados Unidos , Humanos , Flúor , Pandemias , Preparações Farmacêuticas/química , Indústria Farmacêutica , Peptídeos/uso terapêutico , Anticorpos Monoclonais , Produtos Biológicos/uso terapêutico , Produtos Biológicos/química , United States Food and Drug Administration , Oligonucleotídeos/uso terapêutico , PolietilenoglicóisRESUMO
Despite current progress in the development of targeted therapies for cancer treatment, there is a lack in convenient therapeutics for colorectal cancer (CRC). Lactoferrin nanoparticles (Lf NPs) are a promising drug delivery system in cancer therapy. However, numerous obstacles impede their oral delivery, including instability against stomach enzymes and premature uptake during passage through the small intestine. Microencapsulation of Lf NPs offer a great solution for these obstacles. It can protect Lf NPs and their drug payloads from degradation in the upper gastrointestinal tract (GIT), reduce burst drug release, and improve the release profile of the encapsulated NPs triggered by stimuli in the colon. Here, we developed nanoparticle-in-microparticle delivery systems (NIMDs) for the oral delivery of docetaxel (DTX) and atorvastatin (ATR). The NPs were obtained by dual conjugation of DTX and ATR into the Lf backbone, which was further microencapsulated into calcium-crosslinked microparticles using polysaccharide-protein hybrid copolymers. The NIMDs showed no detectable drug release in the upper GIT compared to NPs. Furthermore, sustained release of the NPs from the NIMDs in rat cecal content was observed. Moreover, the in vivo study demonstrated the superiority of the NIMDs over NPs in CRC treatment by suppressing p-AKT, p-ERK1/2, and NF-κB. This study provides the proof of concept for using NIMDs to enhance the effect of protein NPs in CRC treatment.
Assuntos
Antineoplásicos , Neoplasias do Colo , Nanopartículas , Ratos , Animais , Nanoconjugados , Lactoferrina , Docetaxel , Sistemas de Liberação de Medicamentos , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos , Antineoplásicos/farmacologiaRESUMO
Peptide Nucleic Acids (PNAs) are an intriguing class of synthetic biomolecules with great potential in medicine. Although PNAs could be considered analogs of oligonucleotides, their synthesis is more like that of peptides. In both cases, a Solid-Phase Synthesis (SPS) approach is used. Herein, the advantage using Boc as a temporal protecting group has been demonstrated to be more favored than Fmoc. In this context, a new PNA SPS strategy has been developed based on a safety-catch protecting group scheme for the exocyclic nitrogen of the side-chain bases and the linker. Sulfinyl (sulfoxide)-containing moieties are fully stable to the trifluoroacetic acid (TFA) used to remove the Boc group, but they can be reduced to the corresponding sulfide derivatives, which are labile in the presence of TFA. The efficiency of this novel synthetic strategy has been demonstrated in the synthesis of the PNA pentamer H-PNA(TATCT)-ßAla-OH.
Assuntos
Ácidos Nucleicos Peptídicos , Ácidos Nucleicos Peptídicos/química , Peptídeos/químicaRESUMO
While 2021 ended with the world engulfed in the COVID-19 Omicron wave, 2022 has ended in almost all countries, except China, with COVID-19 being likened to the flu. In this context, the U.S. Food and Drug Administration (FDA) has authorized only 37 new drugs this year compared to an average of 52 in the last four years. Thus 2022 is the second lowest harvest after 2016 in the last six years. This ranking may be transient and will be confirmed in the coming years. In this regard, the reduction in the number of drugs accepted by the FDA this year applies only to the so-called small molecules as there has been no variation in the respective numbers of biologics or TIDES (peptides and oligonucleotides). Monoclonal antibodies (mAbs) continue to be the class with the most drugs authorized (9), while proteins/enzymes (5) and an antibody-drug conjugate complete the biologics harvest. In 2022, five TIDES and seven drugs inspired by natural products have received the green light, thus showing the same tendency as in previous years. Finally, pharmaceutical agents with nitrogen aromatic heterocycles and/or fluorine atoms continue to be predominant among small molecules this year. Furthermore, three drugs have been approved for imaging, reinforcing the trend in recent years for this class of treatments. A keyword in 2022 is bispecificity since four drugs have this property (two mAbs, one protein, and one peptide). Herein, the 37 new drugs approved by the FDA in 2022 are analyzed. On the basis of chemical structure alone, these drugs are classified as the following: biologics (antibodies, antibody-drug conjugates, proteins/enzymes), TIDES (peptide and oligonucleotides), combined drugs, natural products; nitrogen aromatic heterocycles, fluorine-containing molecules, and other small molecules.
Assuntos
Produtos Biológicos , COVID-19 , Imunoconjugados , Estados Unidos , Humanos , Aprovação de Drogas , Flúor , Preparações Farmacêuticas/química , Anticorpos Monoclonais/química , Fatores Biológicos , Peptídeos/uso terapêutico , Produtos Biológicos/uso terapêutico , Produtos Biológicos/química , Indústria Farmacêutica , United States Food and Drug Administration , OligonucleotídeosRESUMO
The tropylium ion is a non-benzenoid aromatic species that works as a catalyst. This chemical entity brings about a large number of organic transformations, such as hydroboration reactions, ring contraction, the trapping of enolates, oxidative functionalization, metathesis, insertion, acetalization, and trans-acetalization reactions. The tropylium ion also functions as a coupling reagent in synthetic reactions. This cation's versatility can be seen in its role in the synthesis of macrocyclic compounds and cage structures. Bearing a charge, the tropylium ion is more prone to nucleophilic/electrophilic reactions than neutral benzenoid equivalents. This ability enables it to assist in a variety of chemical reactions. The primary purpose of using tropylium ions in organic reactions is to replace transition metals in catalysis chemistry. It outperforms transition-metal catalysts in terms of its yield, moderate conditions, non-toxic byproducts, functional group tolerance, selectivity, and ease of handling. Furthermore, the tropylium ion is simple to synthesize in the laboratory. The current review incorporates the literature reported from 1950 to 2021; however, the last two decades have witnessed a phenomenal upsurge in the utilization of the tropylium ion in the facilitation of organic conversions. The importance of the tropylium ion as an environmentally safe catalyst in synthesis and a comprehensive summary of some important reactions catalyzed via tropylium cations are described.
RESUMO
Ferrocenyl-based compounds have many applications in diverse scientific disciplines, including in polymer chemistry as redox dynamic polymers and dendrimers, in materials science as bioreceptors, and in pharmacology, biochemistry, electrochemistry, and nonlinear optics. Considering the horizon of ferrocene chemistry, we attempted to condense the neoteric advancements in the synthesis and applications of ferrocene derivatives reported in the literature from 2016 to date. This paper presents data on the progression of the synthesis of diverse classes of organic compounds having ferrocene scaffolds and recent developments in applications of ferrocene-based organometallic compounds, with a special focus on their biological, medicinal, bio-sensing, chemosensing, asymmetric catalysis, material, and industrial applications.
RESUMO
Here, we report the synthesis of disulfide-reducing agents 2-(dibenzylamino) propane-1,3-dithiol (DPDT) and 2-(dibenzylamino)-2-methylpropane-1,3-dithiol (DMPDT) from serinol and methyl serinol, respectively. DPDT was found to show greater stability than DMPDT. Hence, the effectiveness of DPDT as a reducing agent was evaluated in both liquid and solid phases. The reducing capacity of this agent was comparable to that of DTT.
RESUMO
Chemoselective disulfide formation is accomplished through a thiol-disulfide interchange approach using sec-isoamyl mercaptan (SIT) as an alkyl sulfenyl-protecting group of one of the Cys residues involved in the pairing. SIT has a dual and unique characteristic, acting as a masking group during the synthesis and directing disulfide formation in the presence of a free thiol. This novel approach is illustrated by the synthesis of several peptides of biological interest.
Assuntos
Dissulfetos , Compostos de Sulfidrila , PeptídeosRESUMO
Fmoc and Boc group are the two main groups used to protect the α-amino function in Solid-Phase Peptide Synthesis (SPPS). In this regard, the use of the Mmsb linker allows the combination of these two groups. Peptide-O-Mmsb-Resin is stable to the piperidine and trifluoroacetic acid (TFA) treatment used to remove Fmoc and Boc, respectively. The peptide is detached in a two-step protocol, namely reduction of the sulfoxide to the sulfide with Me3SiCl and Ph3P, and then treatment with TFA. The advantage of this strategy has been demonstrated by the following: preparation of peptide with no diketopiperazine formation in sequences prone to this side reaction; on-resin cyclization without the concourse of common organic reagents such as Pd(0) but of difficult use in a biological laboratory; and on-resin disulfide formation in a total side-chain unprotected peptide. The use of Mmsb linker together with Msib (4-(methylsulfinyl)benzyl) and Msbh (4,4'-bis(methylsulfinyl)benzhydryl) described in the accompanying manuscript add a fourth dimension to the SPPS protecting group scheme.
Assuntos
Peptídeos , Técnicas de Síntese em Fase Sólida , Sequência de Aminoácidos , Álcoois Benzílicos , Técnicas de Síntese em Fase Sólida/métodos , Ácido TrifluoracéticoRESUMO
Peptides of importance to both academia and industry are mostly synthesized in the solid-phase mode using a two-dimensional scheme. The so-called Fmoc/tBu strategy, where the groups are removed by piperidine and TFA, respectively, is currently the method of choice for peptide synthesis. However, as the molecular diversity of cyclic and branched peptides becomes a challenging interest, a high level of orthogonal dimensionality is required, such as through triorthogonal protection schemes. Here we present a fourth category of orthogonal protecting groups that are stable under cleavage conditions, including the TFA treatment that removes the tBu-based groups. At the end of the synthetic process and upon some chemical manipulation, the groups in this fourth category were removed with TFA. This new concept of protecting groups could facilitate the synthesis and manipulation of difficult peptides.
Assuntos
Peptídeos , Técnicas de Síntese em Fase Sólida , Peptídeos/química , Técnicas de Síntese em Fase Sólida/métodosRESUMO
Active targeting is a promising approach for the treatment of viral infections. In particular, site-specific formulations for the treatment of HIV infection may overcome challenges associated with current ARV regimens. In this study we explored active targeting by synthesizing a gold nanoparticle construct decorated with an anti-CD4 cyclic peptide. The aim was to demonstrate selectivity of the system for the CD4 receptor and to deliver the RNA payload into T-lymphocytes. Colloidal gold nanoparticles functionalized withN-succinimidyl 3-(2-pyridyldithio) propionate (SPDP) were formed by a one-pot synthesis method where thiol modified polyethyleneimine (PEI) was mixed with chloroauric acid. PEI-SPDP AuNPs (gold nanoparticles) were conjugated to an anti-CD4 peptide and loaded with RNA. We measured toxicity and uptake using TZM-bl and HeLa cells. Our findings show that the nanoparticles bind selectively to CD4 + cells. UV-vis characterisation of the nanoparticles revealed a surface plasmon resonance (SPR) peak at 527 nm, corresponding to a 6 nm diameter. HRTEM of the complete nanoparticles visualised circular shaped particles with average diameter of â¼7 nm. The polydispersity index was calculated to be 0.08, indicating monodispersity of complete NPS in solution. Through the pyridine-2-thione assay each nanoparticle was calculated to carry 1.37 × 105SPDP molecules available for peptide binding. Flow cytometry showed that 13.6% of TZM-bl cells, and 0.14% of HeLa cells retained fluorescence after an overnight incubation, an indication of system binding. No internal RNA delivery was demonstrated. Further work is required to improve internalization.
Assuntos
Infecções por HIV , Nanopartículas Metálicas , Nanopartículas , Ouro , Células HeLa , Humanos , Nanopartículas Metálicas/química , Nanopartículas/química , Peptídeos/farmacologia , Polietilenoimina/química , RNA , Linfócitos TRESUMO
Peptide therapeutics play a key role in the development of new medical treatments. The traditional focus on endogenous peptides has shifted from first discovering other natural sources of these molecules, to later synthesizing those with unique bioactivities. This review provides concise information concerning antimicrobial peptides derived from marine crustaceans for the development of new therapeutics. Marine arthropods do not have an adaptive immune system, and therefore, they depend on the innate immune system to eliminate pathogens. In this context, antimicrobial peptides (AMPs) with unique characteristics are a pivotal part of the defense systems of these organisms. This review covers topics such as the diversity and distribution of peptides in marine arthropods (crustacea and chelicerata), with a focus on penaeid shrimps. The following aspects are covered: the defense system; classes of AMPs; molecular characteristics of AMPs; AMP synthesis; the role of penaeidins, anti-lipopolysaccharide factors, crustins, and stylicins against microorganisms; and the use of AMPs as therapeutic drugs. This review seeks to provide a useful compilation of the most recent information regarding AMPs from marine crustaceans, and describes the future potential applications of these molecules.