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2.
Nat Biotechnol ; 42(3): 518-528, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37231262

RESUMO

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor. OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines.


Assuntos
Vacinas Anticâncer , Vírus da Influenza A , Neoplasias Pulmonares , Animais , Camundongos , Neoplasias Pulmonares/prevenção & controle , Vacinas Anticâncer/genética , Antígenos , Pulmão , Peptídeos , Vacinação , Antígenos de Neoplasias/genética
3.
Nat Rev Cancer ; 24(1): 1, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37749250
4.
Signal Transduct Target Ther ; 8(1): 28, 2023 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690610

RESUMO

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.


Assuntos
Interleucina-2 , Linfócitos T Reguladores , Camundongos , Animais , Subunidade alfa de Receptor de Interleucina-2 , Autoimunidade
5.
Int J Mol Sci ; 23(10)2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35628277

RESUMO

Chitosan oligosaccharide (COS) plays an important role in the growth and development of tea plants. However, responses in tea plants trigged by COS have not been thoroughly investigated. In this study, we integrated transcriptomics and metabolomics analysis to understand the mechanisms of chitosan-induced tea quality improvement and growth promotion. The combined analysis revealed an obvious link between the flourishing development of the tea plant and the presence of COS. It obviously regulated the growth and development of the tea and the metabolomic process. The chlorophyll, soluble sugar, and amino acid content in the tea leaves was increased. The phytohormones, carbohydrates, and amino acid levels were zoomed-in in both transcript and metabolomics analyses compared to the control. The expression of the genes related to phytohormones transduction, carbon fixation, and amino acid metabolism during the growth and development of tea plants were significantly upregulated. Our findings indicated that alerted transcriptomic and metabolic responses occurring with the application of COS could cause efficiency in substrates in pivotal pathways and hence, elicited plant growth.


Assuntos
Camellia sinensis , Quitosana , Aminoácidos/metabolismo , Camellia sinensis/metabolismo , Quitosana/metabolismo , Regulação da Expressão Gênica de Plantas , Metabolômica , Oligossacarídeos/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/genética , Chá/genética , Chá/metabolismo , Transcriptoma
6.
Insects ; 12(12)2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34940220

RESUMO

This study aimed to clarify the functional response and control potential of O. sauteri in relation to tea thrips. The functional response, interference response, and control potential of O. sauteri on adult tea thrips, in different insect stages and environment temperatures, were studied. The results showed that the predation of O. sauteri against tea thrips was positively correlated with prey density, while the effects of searching for O. sauteri on the adult tea thrips were negatively correlated with prey density. The predation effects of O. sauteri on tea thrips were also influenced by prey density, which indicated that there was an intra-specific interference response from predators to tea thrips. The population density of tea thrips was significantly decreased, and O. sauteri showed a remarkable ability to control them when the benefit-to-harm ratio was 3:100.

7.
Nat Biomed Eng ; 5(11): 1288-1305, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34580438

RESUMO

The preferential activation of regulatory T (Treg) cells by interleukin-2 (IL-2), which selectively binds to the trimeric IL-2 receptor (IL-2R) on Treg cells, makes this cytokine a promising therapeutic for the treatment of autoimmune diseases. However, IL-2 has a narrow therapeutic window and a short half-life. Here, we show that the pharmacokinetics and half-life of IL-2 can be substantially improved by orthogonally conjugating the cytokine to poly(ethylene glycol) (PEG) moieties via a copper-free click reaction through the incorporation of azide-bearing amino acids at defined sites. Subcutaneous injection of a PEGylated IL-2 that optimally induced sustained Treg-cell activation and expansion over a wide range of doses through highly selective binding to trimeric IL-2R led to enhanced therapeutic efficacy in mouse models of lupus, collagen-induced arthritis and graft-versus-host disease without compromising the immune defences of the host against viral infection. Site-specific PEGylation could be used more generally to engineer cytokines with improved therapeutic performance for the treatment of autoimmune diseases.


Assuntos
Interleucina-2 , Linfócitos T Reguladores , Animais , Citocinas , Tolerância Imunológica , Terapia de Imunossupressão , Camundongos
8.
Insects ; 12(2)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672847

RESUMO

Tea green leafhoppers and thrips are key pests in tea plantations and have widely invaded those of Asian origin. Pesticides are currently a favorable control method but not desirable for frequent use on tea plants. To meet Integrated Pest Management (IPM) demand, biological control with a natural enemy is viewed as the most promising way. Orius sauteri are slated to be a natural enemy to tea pests. However, more knowledge of rearing O. sauteri and selecting banker plant systems is strongly needed. The reproductive biology evaluation of the egg oviposition and population life parameters of O. sauteri under laboratory conditions were examined, and the supporting ability of 11 plant species-motherwort, white clover, red bean, mung bean, peanut, soybean, kidney bean, herba violae, bush vetch, smooth vetch, and common vetch-in a greenhouse was assessed. Most of the selected plants, except for herba violae, performed relatively well with high oviposition quantity and survival. The mean fecundity per female on red bean and motherwort was 148.75 eggs and 148.25 eggs, respectively, and 90.20 eggs for tea plants (the smallest); there also were significant differences. In an experiment to determine the life parameters of O. sauteri, all the tested plants, except herba violae, were found to be able to complete the growth and development of the life cycle; there also were significant differences. The intrinsic rate of increase of motherwort and red bean was 1.18 and 1.17, respectively, and higher compared to that of the other plants, including tea plants (1.13). This result of the O. sauteri population development index was also confirmed in a greenhouse with the number of motherwort and red beans being as high as 113.33 and 112.67. Since motherwort was found to be susceptible to aphids and powdery mildew in each trial, it cannot be used for intercropping in tea gardens. Among the 11 plants, red bean was found to be the most suitable to support O. sauteri in tea plantations.

9.
Bioorg Med Chem ; 28(6): 115354, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32063403

RESUMO

A series of anthranilamide derivatives were designed and synthesized as novel smoothened (SMO) inhibitors based on the SMO inhibitor taladegib (LY2940680), which can also inhibit the SMO-D473H mutant, via a ring-opening strategy. The phthalazine core in LY2940680 was replaced with anthranilamide, which retained the inhibitory activity towards the hedgehog (Hh) signaling pathway as evidenced by a dual luciferase reporter gene assay. Compound 12a displayed the best inhibitory activity against the Hh signaling pathway with IC50 value of 34.09 nM, and exhibited better proliferation inhibitory activity towards the Daoy cell line (IC50 = 0.48 µM) than LY2940680 (IC50 = 0.79 µM).


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Receptor Smoothened/antagonistas & inibidores , ortoaminobenzoatos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química
10.
Eur J Med Chem ; 164: 334-341, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30605831

RESUMO

Constitutive activation of MAPK (RAS/RAF/MEK/ERK) pathway is frequently observed in many tumors and thus has become an interesting therapeutic target for cancer therapy. Despite the successful development of BRAF and MEK inhibitors in clinic treatment, resistance often appears to re-enhance ERK1/2 signaling. Inspired by the central role of the ERK1/2 signaling cascade in cancer, we describe the scaffold-hopping generation of a series of isoindolin-1-one ERK1/2 inhibitors. Our new compounds could inhibit proliferation of KRAS and BRAF mutant cells lines at low nanomolar concentrations. Compound 22a possesses acceptable pharmacokinetic profiles and showed considerable in vivo antitumor efficacy in a HCT-116 xenograft model, providing a promising basis for further optimization towards clinical ERK1/2 inhibitors.


Assuntos
Descoberta de Drogas , Isoindóis/química , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Animais , Disponibilidade Biológica , Linhagem Celular , Desenho de Fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Relação Estrutura-Atividade
12.
Org Lett ; 18(18): 4478-81, 2016 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-27584913

RESUMO

An efficient and facile process was developed for the remote C-H bond amidation of 8-aminoquinoline scaffolds on the C5 position which is geometric. The method only made use of PhI(OAc)2 as a mediator and showed good tolerance toward numerous dibenzenesulfonimides and amides, giving the corresponding products in moderate to excellent yield.

13.
Bioorg Med Chem Lett ; 26(16): 4127-32, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27353531

RESUMO

A series of novel 5-fluorine-benzimidazole-4-carboxamide analogs were designed and synthesized. All target compounds were evaluated for their PARP-1 inhibitory activity. Compounds possessed high intrinsic PARP-1 inhibitory potency have been evaluated in vitro cellular assays to measure the potentiation effect of cytotoxic agents against cancer cell line. These efforts led to the identification of compound 10f, which displayed strong inhibition against the PARP-1 enzyme with an IC50 of 43.7nM, excellent cell inhibitory activity in HCT116 cells (IC50=7.4µM) and potentiation of temozolomide cytotoxicity in cancer cell line A549 (PF50=1.6).


Assuntos
Amidas/química , Antineoplásicos/síntese química , Benzimidazóis/química , Benzimidazóis/síntese química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Células A549 , Amidas/síntese química , Amidas/toxicidade , Antineoplásicos/química , Antineoplásicos/toxicidade , Benzimidazóis/toxicidade , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/toxicidade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Células HCT116 , Humanos , Simulação de Acoplamento Molecular , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Temozolomida
14.
Org Lett ; 17(15): 3798-801, 2015 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-26172446

RESUMO

A novel and facile process for direct fluorination of unactivated C(sp3)-H bonds at the ß position of carboxylic acids was accomplished by a palladium(II)-catalyzed C-H activation. The addition of Ag2O and pivalic acid was found to be crucial for the success of this transformation. This reaction provides a versatile strategy for the synthesis of ß-fluorinated carboxylic acids.

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