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1.
Nat Commun ; 15(1): 6214, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39043660

RESUMEN

Protein-protein interactions (PPIs) are central in cell metabolism but research tools for the structural and functional characterization of these PPIs are often missing. Here we introduce broadly applicable immunization (Cross-link PPIs and immunize llamas, ChILL) and selection strategies (Display and co-selection, DisCO) for the discovery of diverse nanobodies that either stabilize or disrupt PPIs in a single experiment. We apply ChILL and DisCO to identify competitive, connective, or fully allosteric nanobodies that inhibit or facilitate the formation of the SOS1•RAS complex and modulate the nucleotide exchange rate on this pivotal GTPase in vitro as well as RAS signalling in cellulo. One of these connective nanobodies fills a cavity that was previously identified as the binding pocket for a series of therapeutic lead compounds. The long complementarity-determining region (CDR3) that penetrates this binding pocket serves as pharmacophore for extending the repertoire of potential leads.


Asunto(s)
Unión Proteica , Proteína SOS1 , Anticuerpos de Dominio Único , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología , Anticuerpos de Dominio Único/metabolismo , Proteína SOS1/metabolismo , Proteína SOS1/química , Proteína SOS1/genética , Proteína SOS1/inmunología , Humanos , Animales , Regulación Alostérica , Proteínas ras/metabolismo , Proteínas ras/química , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/inmunología , Sitios de Unión , Camélidos del Nuevo Mundo/inmunología , Inmunización , Transducción de Señal , Modelos Moleculares
2.
Trends Pharmacol Sci ; 45(7): 579-582, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38724411

RESUMEN

Peptide arrays are a valuable instrument in the characterization of protein-protein interactions (PPIs) and immunogenic regions. New methods were developed to exploit the high-throughput potential of peptide arrays to obtain more in-depth information, replacing traditional resource-intensive experiments. Here, we discuss the recent advances in peptide-array-based technologies and the remaining challenges.


Asunto(s)
Mapeo Epitopo , Ensayos Analíticos de Alto Rendimiento , Biblioteca de Péptidos , Humanos , Mapeo Epitopo/métodos , Análisis por Matrices de Proteínas/métodos , Animales
3.
J Med Chem ; 67(9): 7603-7619, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38687204

RESUMEN

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.


Asunto(s)
Receptores de Neuropéptido , Receptores Opioides mu , Animales , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/metabolismo , Ratones , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismo , Masculino , Analgésicos/farmacología , Analgésicos/química , Analgésicos/uso terapéutico , Analgésicos/síntesis química , Humanos , Relación Estructura-Actividad , Analgésicos Opioides/farmacología , Analgésicos Opioides/química
4.
Macromol Biosci ; 24(8): e2300579, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38552257

RESUMEN

Throughout the past decades, amphipathic peptide-based hydrogels have proven to be promising materials for biomedical applications. Amphipathic peptides are known to adopt ß-sheet configurations that self-assemble into fibers that then interact to form a hydrogel network. A fundamental understanding of how the peptide sequence alters the structural properties of the hydrogels would allow for a more rational design of novel peptides for a variety of biomedical applications in the future. Therefore, the current work investigates how changing the type of amino acid, the amphipathic pattern, and the peptide length affects the secondary structure, fiber characteristics, and stiffness of peptide-based hydrogels. Hereto, seven amphipathic peptides of different sequence and length, four of which have not been previously reported, based on and including the hexapeptide H-Phe-Gln-Phe-Gln-Phe-Lys-NH2, are synthesized and thoroughly characterized by circular dichroism (CD), Fourier Transform Infrared (FTIR) spectroscopy, Wide Angle X-ray Scattering (WAXS), Small Angle X-ray Scattering (SAXS), Transmission Electron Microscopy (TEM), and Thioflavin T (ThT) fibrillization assays. The results show that a high amount of regularly spaced ß-sheets, a high amount of fibers, and fiber bundling contribute to the stiffness of the hydrogel. Furthermore, a study of the time-dependent fibril formation process reveals complex transient dynamics. The peptide strands structure through an intermediate helical state prior to ß-sheet formation, which is found to be concentration- and time-dependent.


Asunto(s)
Hidrogeles , Hidrogeles/química , Péptidos/química , Secuencia de Aminoácidos , Dicroismo Circular , Estructura Secundaria de Proteína , Espectroscopía Infrarroja por Transformada de Fourier
5.
J Med Chem ; 67(4): 2690-2711, 2024 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-38345933

RESUMEN

Melanocortin 4 receptor (MC4-R) antagonists are actively sought for treating cancer cachexia. We determined the structures of complexes with PG-934 and SBL-MC-31. These peptides differ from SHU9119 by substituting His6 with Pro6 and inserting Gly10 or Arg10. The structures revealed two subpockets at the TM7-TM1-TM2 domains, separated by N2857.36. Two peptide series based on the complexed peptides led to an antagonist activity and selectivity SAR study. Most ligands retained the SHU9119 potency, but several SBL-MC-31-derived peptides significantly enhanced MC4-R selectivity over MC1-R by 60- to 132-fold. We also investigated MC4-R coupling to the K+ channel, Kir7.1. Some peptides activated the channel, whereas others induced channel closure independently of G protein coupling. In cell culture studies, channel activation correlated with increased feeding, while a peptide with Kir7.1 inhibitory activity reduced eating. These results highlight the potential for targeting the MC4-R:Kir7.1 complex for treating positive and restrictive eating disorders.


Asunto(s)
Péptidos , Receptor de Melanocortina Tipo 4 , Humanos , Péptidos/farmacología , Ligandos , Diseño de Fármacos , Receptor de Melanocortina Tipo 3 , Receptores de Melanocortina
6.
Eur J Pharm Biopharm ; 196: 114183, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38246566

RESUMEN

Monoclonal antibodies (mAbs) targeting the immune checkpoint axis, which contains the programmed cell death protein-1 (PD-1) and its ligand PD-L1, revolutionized the field of oncology. Unfortunately, the large size of mAbs and the presence of an Fc fraction limit their tumor penetrative capacities and support off-target effects, potentially resulting in unresponsive patients and immune-related adverse events (irAEs) respectively. Single-domain antibodies (sdAbs) are ten times smaller than conventional mAbs and represent an emerging antibody subclass that has been proposed as next generation immune checkpoint inhibitor (ICI) therapeutics. They demonstrate favorable characteristics, such as an excellent stability, high antigen-binding affinity and an enhanced tumor penetration. Because sdAbs have a short half-life, methods to prolong their presence in the circulation and at the target site might be necessary in some cases to unfold their full therapeutic potential. In this study, we investigated a peptide-based hydrogel as an injectable biomaterial depot formulation for the sustained release of the human PD-L1 sdAb K2. We showed that a hydrogel composed of the amphipathic hexapeptide hydrogelator H-FQFQFK-NH2 prolonged the in vivo release of K2 after subcutaneous (s.c.) injection, up to at least 72 h, as monitored by SPECT/CT and fluorescence imaging. Additionally, after encapsulation in the hydrogel and s.c. administration, a significantly extended systemic presence and tumor uptake of K2 was observed in mice bearing a melanoma tumor expressing human PD-L1. Altogether, this study describes how peptide hydrogels can be exploited to provide the sustained release of sdAbs, thereby potentially enhancing its clinical and therapeutic effects.


Asunto(s)
Melanoma , Anticuerpos de Dominio Único , Humanos , Animales , Ratones , Preparaciones de Acción Retardada , Antígeno B7-H1/metabolismo , Hidrogeles , Péptidos/química , Anticuerpos Monoclonales/uso terapéutico , Melanoma/tratamiento farmacológico
7.
bioRxiv ; 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-38106026

RESUMEN

The µ-opioid receptor (µOR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and fentanyl. Due to the limitations and severe side effects of currently available opioid drugs, there is considerable interest in developing novel modulators of µOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, are emerging as alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the µOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded µOR ligand and uncover the molecular basis for µOR antagonism by solving the cryo-EM structure of the NbE-µOR complex. NbE displays a unique ligand binding mode and achieves µOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a ß-hairpin loop formed by NbE that deeply inserts into the µOR and centers most binding contacts, we design short peptide analogues that retain µOR antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes novel µOR ligands that can serve as a basis for therapeutic developments.

8.
J Med Chem ; 66(18): 13086-13102, 2023 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-37703077

RESUMEN

Following a rational design, a series of macrocyclic ("stapled") peptidomimetics of 10Panx1, the most established peptide inhibitor of Pannexin1 (Panx1) channels, were developed and synthesized. Two macrocyclic analogues SBL-PX1-42 and SBL-PX1-44 outperformed the linear native peptide. During in vitro adenosine triphosphate (ATP) release and Yo-Pro-1 uptake assays in a Panx1-expressing tumor cell line, both compounds were revealed to be promising bidirectional inhibitors of Panx1 channel function, able to induce a two-fold inhibition, as compared to the native 10Panx1 sequence. The introduction of triazole-based cross-links within the peptide backbones increased helical content and enhanced in vitro proteolytic stability in human plasma (>30-fold longer half-lives, compared to 10Panx1). In adhesion assays, a "double-stapled" peptide, SBL-PX1-206 inhibited ATP release from endothelial cells, thereby efficiently reducing THP-1 monocyte adhesion to a TNF-α-activated endothelial monolayer and making it a promising candidate for future in vivo investigations in animal models of cardiovascular inflammatory disease.


Asunto(s)
Enfermedades Cardiovasculares , Conexinas , Animales , Humanos , Conexinas/metabolismo , Células Endoteliales/metabolismo , Línea Celular Tumoral , Péptidos/farmacología , Péptidos/uso terapéutico , Adenosina Trifosfato/metabolismo
9.
J Control Release ; 362: 138-150, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37619864

RESUMEN

Postoperative peritoneal adhesions occur in the majority of patients undergoing intra-abdominal surgery and are one of the leading causes of hospital re-admission. There is an unmet clinical need for effective anti-adhesive biomaterials, which can be applied evenly across the damaged tissues. We examined three different responsive hydrogel types, i.e. a thermosensitive PLGA-PEG-PLGA, a pH responsive UPy-PEG and a shear-thinning hexapeptide for this purpose. More specifically, their potential to be homogeneously distributed in the peritoneal cavity by high pressure nebulization and prevent peritoneal adhesions was evaluated. Solutions of each polymer type could be successfully nebulized while retaining their responsive gelation behavior in vitro and in vivo. Furthermore, none of the polymers caused in vitro toxicity on SKOV3-IP2 cells. Following intraperitoneal administration, both the PLGA-PEG-PLGA and the hexapeptide hydrogels resulted in local inflammation and fibrosis and failed in preventing peritoneal adhesions 7 days after adhesion induction. In contrast, the pH sensitive UPy-PEG formulation was well tolerated and could significantly reduce the formation of peritoneal adhesions, even outperforming the commercially available Hyalobarrier® as positive control. To conclude, local nebulization of the bioresponsive UPy-PEG hydrogel can be considered as a promising approach to prevent postsurgical peritoneal adhesions.

10.
Bioorg Chem ; 139: 106731, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37480815

RESUMEN

Over the past decades, many cell-penetrating peptides (CPP) have been studied for their capacity to cross cellular membranes, mostly in order to improve cellular uptake of therapeutic agents. Even though hydrophobic and anionic CPPs have been described, many of them are polycationic, due to the presence of several arginine (Arg) residues. Noteworthy, however, the presence of aromatic amino acids such as tryptophan (Trp) within CPPs seems to play an important role to reach high membranotropic activity. RW9 (RRWWRRWRR) is a designed CPP derived from the polyarginine R9 presenting both features. In general, when interacting with membranes, CPPs adopt an optimal conformation for membrane interactions - an amphipathic helical secondary structure in the case of RW9. Herein, we assumed that the incorporation of a locally constrained amino acid in the peptide sequence could improve the membranotropic activity of RW9, by facilitating its structuration upon contact with a membrane, while leaving a certain plasticity. Therefore, two cyclized Trp derivatives (Tcc and Aia) were synthesized to be incorporated in RW9 as surrogates of Trp residues. Thus, a series of peptides containing these building blocks has been synthesized by varying the type, position, and number of modifications. The membranotropic activity of the RW9 analogs was studied by spectrofluorescence titration of the peptides in presence of liposomes (DMPG), allowing to calculate partition coefficients (Kp). Our results indicate that the partitioning of the modified peptides depends on the type, the number and the position of the modification, with the best sequence being [Aia4]RW9. Interestingly, both NMR analysis and molecular dynamic (MD) simulations indicate that this analog presents an extended conformation similar to the native RW9, but with a much-reduced structural flexibility. Finally, cell internalization properties were also confirmed by confocal microscopy.


Asunto(s)
Péptidos de Penetración Celular , Péptidos de Penetración Celular/farmacología , Péptidos de Penetración Celular/química , Membrana Celular/metabolismo , Secuencia de Aminoácidos , Liposomas/química , Simulación de Dinámica Molecular
11.
Antiviral Res ; 217: 105675, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37481039

RESUMEN

Human T-cell leukemia virus type-1 (HTLV-1) is the first pathogenic retrovirus discovered in human. Although HTLV-1-induced diseases are well-characterized and linked to the encoded Tax-1 oncoprotein, there is currently no strategy to target Tax-1 functions with small molecules. Here, we analyzed the binding of Tax-1 to the human homolog of the drosophila discs large tumor suppressor (hDLG1/SAP97), a multi-domain scaffolding protein involved in Tax-1-transformation ability. We have solved the structures of the PDZ binding motif (PBM) of Tax-1 in complex with the PDZ1 and PDZ2 domains of hDLG1 and assessed the binding of 10 million molecules by virtual screening. Among the 19 experimentally confirmed compounds, one systematically inhibited the Tax-1-hDLG1 interaction in different biophysical and cellular assays, as well as HTLV-1 cell-to-cell transmission in a T-cell model. Thus, our work demonstrates that interactions involving Tax-1 PDZ-domains are amenable to small-molecule inhibition, which provides a framework for the design of targeted therapies for HTLV-1-induced diseases.


Asunto(s)
Virus Linfotrópico T Tipo 1 Humano , Humanos , Antivirales/farmacología , Antivirales/metabolismo , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Dominios PDZ , Proteínas , Linfocitos T/metabolismo
12.
Bioorg Chem ; 138: 106612, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37210827

RESUMEN

Pannexin1 channels facilitate paracrine communication and are involved in a broad spectrum of diseases. Attempts to find appropriate pannexin1 channel inhibitors that showcase target-selective properties and in vivo applicability remain nonetheless scarce. However, a promising lead candidate, the ten amino acid long peptide mimetic 10Panx1 (H-Trp1-Arg2-Gln3-Ala4-Ala5-Phe6-Val7-Asp8-Ser9-Tyr10-OH), has shown potential as a pannexin1 channel inhibitor in both in vitro and in vivo studies. Nonetheless, structural optimization is critical for clinical use. One of the main hurdles to overcome along the optimization process consists of subduing the low biological stability (10Panx1 t1/2 = 2.27 ± 0.11 min). To tackle this issue, identification of important structural features within the decapeptide structure is warranted. For this reason, a structure-activity relationship study was performed to proteolytically stabilize the sequence. Through an Alanine scan, this study demonstrated that the side chains of Gln3 and Asp8 are crucial for 10Panx1's channel inhibitory capacity. Guided by plasma stability experiments, scissile amide bonds were identified and stabilized, while extracellular adenosine triphosphate release experiments, indicative of pannexin1 channel functionality, allowed to enhance the in vitro inhibitory capacity of 10Panx1.


Asunto(s)
Fragmentos de Péptidos , Péptidos , Secuencia de Aminoácidos , Péptidos/farmacología , Aminoácidos , Alanina
13.
Angew Chem Int Ed Engl ; 62(24): e202219095, 2023 06 12.
Artículo en Inglés | MEDLINE | ID: mdl-37067463

RESUMEN

RAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active guanosine triphosphate (GTP)-bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14 (Nb14), which potently enhances SOS1-catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity-determining region 3 (CDR3). Guided by a biochemical GEF assay and X-ray co-crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of Nb14 with an EC50 value of 29 µM. Altogether, this study demonstrated that peptides able to modulate a protein-protein interaction can be obtained by structural mimicry of a Nb paratope.


Asunto(s)
Núcleo Familiar , Nucleótidos , Transducción de Señal , Factores de Intercambio de Guanina Nucleótido/metabolismo , Catálisis
14.
Nucleic Acids Res ; 51(7): 3420-3435, 2023 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-36864742

RESUMEN

Obg is a widely conserved and essential GTPase in bacteria, which plays a central role in a large range of important cellular processes, such as ribosome biogenesis, DNA replication, cell division and bacterial persistence. Nevertheless, the exact function of Obg in these processes and the interactions it makes within the associated pathways remain largely unknown. Here, we identify the DNA-binding TrpD2 protein YbiB as an interactor of the Escherichia coli Obg (ObgE). We show that both proteins interact with high affinity in a peculiar biphasic fashion, and pinpoint the intrinsically disordered and highly negatively charged C-terminal domain of ObgE as a main driver for this interaction. Molecular docking and X-ray crystallography, together with site-directed mutagenesis, are used to map the binding site of this ObgE C-terminal domain within a highly positively charged groove on the surface of the YbiB homodimer. Correspondingly, ObgE efficiently inhibits the binding of DNA to YbiB, indicating that ObgE competes with DNA for binding in the positive clefts of YbiB. This study thus forms an important step for the further elucidation of the interactome and cellular role of the essential bacterial protein Obg.


Asunto(s)
Proteínas de Escherichia coli , Proteínas de Unión al GTP Monoméricas , Proteínas de Escherichia coli/metabolismo , Proteínas de Unión al GTP Monoméricas/genética , Simulación del Acoplamiento Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Bacterianas/metabolismo , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo
15.
Biomacromolecules ; 24(4): 1638-1647, 2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-36949571

RESUMEN

In an attempt to mimic nature's ability to adhere cells, PCL is often coated with nature-derived polymers or its surface is functionalized with a cell-binding motif. However, said surface modifications are limited to the material's surface, include multiple steps, and are mediated by harsh conditions. Here, we introduce a single-step strategy toward cell-adhesive polymer networks where thiol-ene chemistry serves a dual purpose. First, alkene-functionalized PCL is crosslinked by means of a multifunctional thiol. Second, by means of a cysteine coupling site, the cell-binding motif C(-linker-)RGD is covalently bound throughout the PCL networks during crosslinking. Moreover, the influence of various linkers (type and length), between the cysteine coupling site and the cell-binding motif RGD, is investigated and the functionalization is assessed by means of static contact angle measurements and X-ray photoelectron spectroscopy. Finally, successful introduction of cell adhesiveness is illustrated for the networks by seeding fibroblasts onto the functionalized PCL networks.


Asunto(s)
Cisteína , Compuestos de Sulfhidrilo , Compuestos de Sulfhidrilo/química , Polímeros/química , Alquenos , Oligopéptidos/química
16.
ACS Pharmacol Transl Sci ; 6(2): 290-305, 2023 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-36798478

RESUMEN

Apelin is an endogenous peptide that is involved in many diseases such as cardiovascular diseases, obesity, and cancer, which has made it an attractive target for drug discovery. Herein, we explore the penultimate and final sequence positions of [Pyr1]-apelin-13 (Ape13) via C-terminal N α-alkylated amide bonds and the introduction of positive charges, potentially targeting the allosteric sodium pocket, by assessing the binding affinity and signaling profiles at the apelin receptor (APJ). Synthetic analogues modified within this segment of Ape13 showed high affinity (K i 0.12-0.17 nM vs Ape13 K i 0.7 nM), potent Gαi1 activation (EC50 Gαi1 0.4-0.9 nM vs Ape13 EC50 1.1 nM), partial agonist behavior disfavoring ß-arrestin 2 recruitment for positively charged ligands (e.g., 49 (SBL-AP-058), EC50 ß-arr2 275 nM, E max 54%) and high plasma stability for N-alkyl ligands (t 1/2 > 7 h vs Ape13 t 1/2 0.5 h). Combining the benefits of the N α-alkylated amide bond with the guanidino substitution in a constrained ligand led to 63 (SBL-AP-049), which displayed increased plasma stability (t 1/2 5.3 h) and strong reduction of ß-arrestin 2 signaling with partial maximal efficacy (EC50 ß-arr 864 nM, E max 48%), significantly reducing the hypotensive effect in vivo.

17.
Small ; 19(20): e2206795, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36807731

RESUMEN

Peptide-based hydrogels are promising biocompatible materials for wound healing, drug delivery, and tissue engineering applications. The physical properties of these nanostructured materials depend strongly on the morphology of the gel network. However, the self-assembly mechanism of the peptides that leads to a distinct network morphology is still a subject of ongoing debate, since complete assembly pathways have not yet been resolved. To unravel the dynamics of the hierarchical self-assembly process of the model ß-sheet forming peptide KFE8 (Ac-FKFEFKFE-NH2 ), high-speed atomic force microscopy (HS-AFM) in liquid is used. It is demonstrated that a fast-growing network, based on small fibrillar aggregates, is formed at a solid-liquid interface, while in bulk solution, a distinct, more prolonged nanotube network emerges from intermediate helical ribbons. Moreover, the transformation between these morphologies has been visualized. It is expected that this new in situ and in real-time methodology will set the path for the in-depth unravelling of the dynamics of other peptide-based self-assembled soft materials, as well as gaining advanced insights into the formation of fibers involved in protein misfolding diseases.


Asunto(s)
Nanoestructuras , Péptidos , Conformación Proteica en Lámina beta , Péptidos/química , Nanoestructuras/química , Sistemas de Liberación de Medicamentos , Microscopía de Fuerza Atómica
18.
Bioorg Med Chem Lett ; 79: 129066, 2023 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-36410591

RESUMEN

Treatment of advanced stage epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is often complicated by the occurrence of acquired resistance, which emphasizes the need for improved treatment options. Based on a previously reported structure-activity relationship (SAR) study of Spautin-1, which resulted in the discovery of 10a, the search for more potent analogues was envisaged through optimization of the amine substituent. Our search led to the discovery of analogue 15b, harbouring the 2-[4-(4-fluoro-phenoxy)-phenyl]ethylamine substituent, among other potent and original analogues, with nanomolar activity towards EGFR-mutant NSCLC cells. Moreover, this compound 15b showed good selectivity for cancer cells over healthy lung epithelial cells and provides additive effects with food and drug administration (FDA) approved EGFR-tyrosine kinase inhibitors (TKIs), as proven by the co-administration of 15b with Afatinib. Altogether, we report promising lead compounds which show the potential to improve current treatment options.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/química , Quinazolinas/farmacología
19.
J Pept Sci ; 29(6): e3471, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36539999

RESUMEN

Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of µ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and nonselective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results.


Asunto(s)
Manejo del Dolor , Receptores de Neurotensina , Humanos , Receptores de Neurotensina/agonistas , Receptores de Neurotensina/metabolismo , Aminoácidos , Analgésicos Opioides/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Péptidos/química , Neurotensina/metabolismo , Dolor/tratamiento farmacológico , Ligandos
20.
Org Lett ; 25(1): 130-133, 2023 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-36546856

RESUMEN

Herein, alkylated propargylamines are reported as constrained lysine mimetics and constructed in a single step using a copper(I)-catalyzed A3-coupling reaction. Using multiple secondary amines, the reaction allowed the generation of a structurally diverse set of N-Fmoc protected amino acid derivatives. In addition, the A3-reaction was applied on solid phase via the assembly of short model tripeptides. Moreover, the internal alkyne moiety allowed further functionalization toward novel 1,4,5-trisubstituted 1,2,3-triazole-based amino acids.


Asunto(s)
Aminoácidos , Lisina , Aminoácidos/química , Aminas/química , Propilaminas
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