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1.
ACS Med Chem Lett ; 15(6): 828-836, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38894909

RESUMO

Therapeutic antibodies directed against either programmed cell death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy in the treatment of various cancers. In contrast with antibodies, small molecules have the potential for increased tissue penetration; better pharmacology; and therefore, improved antitumor activity. A series of nonsymmetric C2 inhibitors were synthesized and evaluated for PD-1/PD-L1 interaction inhibition. These compounds induced PD-L1 dimerization and effectively blocked PD-L1/PD-1 interaction in a homogeneous time-resolved fluorescence (HTRF) assay with most inhibitors exhibiting IC50 values in the single-digit nM range and below. Their high inhibitory potency was also demonstrated in a cell-based coculture PD-1 signaling assay where 2 exhibited an EC50 inhibitory activity of 21.8 nM, which approached that of the PD-L1 antibody durvalumab (EC50 = 0.3-1.8 nM). Structural insight into how these inhibitors interact with PD-L1 was gained by using NMR and X-ray cocrystal structure studies. These data support further preclinical evaluation of these compounds as antibody alternatives.

3.
Expert Opin Ther Pat ; 34(8): 627-650, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38903044

RESUMO

INTRODUCTION: PD-L1, via its interactions with PD-1, constitutes a key immune checkpoint that allows cancer cells to escape immune surveillance. Targeting PD-1/PD-L1 with monoclonal antibodies (mAbs) led to spectacular success in clinical oncology. However, the inherent limitations of mAbs and increasing findings about immune-related adverse events (iRAEs) prompted intense research in the field of small-molecule inhibitors of PD-L1. AREAS COVERED: This review covers inhibitors of PD-L1 reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2022-2023 period. This review provides a landscape of available inhibitors, including their chemical structures, activity, and stage of development. EXPERT OPINION: Small-molecule inhibitors impairing PD-L1/PD-1 interaction represent an attractive alternative to mAbs. In recent years, the field of small-molecule and macrocyclic inhibitors targeting PD-L1 has grown rapidly. The majority (if not all) of small-molecule inhibitors developed recently, similarly to their predecessors, act through a dimerization mechanism of PD-L1, followed by its internalization into the cytosol. In contrast, macrocyclic peptides act purely through a competition mechanism known as protein-protein interaction inhibitors. The ongoing clinical trials should ultimately reveal which strategy has real clinical potential and may complement or even replace mAbs-based therapies.


Assuntos
Antígeno B7-H1 , Desenvolvimento de Medicamentos , Inibidores de Checkpoint Imunológico , Neoplasias , Patentes como Assunto , Receptor de Morte Celular Programada 1 , Humanos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/farmacologia
4.
Front Immunol ; 15: 1399459, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38812508

RESUMO

Initiation of the bradykinin generation cascade is responsible for the occurrence of attacks in some types of angioedema without wheals. Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) is one such clinical entity. In this paper, we explore the existing evidence that mast cells (MCs) degranulation may contribute to the activation of the kallikrein-kinin system cascade, followed by bradykinin formation and angioedema. We present the multidirectional effects of MC-derived heparin and other polyanions on the major components of the kinin-kallikrein system, particularly on the factor XII activation. Although, bradykinin- and histamine-mediated symptoms are distinct clinical phenomena, they share some common features, such as some similar triggers and a predilection to occur at sites where mast cells reside, namely the skin and mucous membranes. In addition, recent observations indicate a high incidence of hypersensitivity reactions associated with MC degranulation in the HAE-C1-INH patient population. However, not all of these can be explained by IgE-dependent mechanisms. Mast cell-related G protein-coupled receptor-X2 (MRGPRX2), which has recently attracted scientific interest, may be involved in the activation of MCs through a different pathway. Therefore, we reviewed MRGPRX2 ligands that HAE-C1-INH patients may be exposed to in their daily lives and that may affect MCs degranulation. We also discussed the known inter- and intra-individual variability in the course of HAE-C1-INH in relation to factors responsible for possible variability in the strength of the response to MRGPRX2 receptor stimulation. The above issues raise several questions for future research. It is not known to what extent a prophylactic or therapeutic intervention targeting the pathways of one mechanism (mast cell degranulation) may affect the other (bradykinin production), or whether the number of mast cells at a specific body site and their reactivity to triggers such as pressure, allergens or MRGPRX2 agonists may influence the occurrence of HAE-C1-INH attacks at that site.


Assuntos
Bradicinina , Degranulação Celular , Mastócitos , Receptores Acoplados a Proteínas G , Receptores de Neuropeptídeos , Humanos , Mastócitos/imunologia , Mastócitos/metabolismo , Bradicinina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Angioedema/metabolismo , Angioedema/imunologia , Angioedema/etiologia , Proteínas do Tecido Nervoso/metabolismo , Sistema Calicreína-Cinina/fisiologia
5.
Nat Comput Sci ; 4(5): 367-378, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38730184

RESUMO

Large language models have greatly enhanced our ability to understand biology and chemistry, yet robust methods for structure-based drug discovery, quantum chemistry and structural biology are still sparse. Precise biomolecule-ligand interaction datasets are urgently needed for large language models. To address this, we present MISATO, a dataset that combines quantum mechanical properties of small molecules and associated molecular dynamics simulations of ~20,000 experimental protein-ligand complexes with extensive validation of experimental data. Starting from the existing experimental structures, semi-empirical quantum mechanics was used to systematically refine these structures. A large collection of molecular dynamics traces of protein-ligand complexes in explicit water is included, accumulating over 170 µs. We give examples of machine learning (ML) baseline models proving an improvement of accuracy by employing our data. An easy entry point for ML experts is provided to enable the next generation of drug discovery artificial intelligence models.


Assuntos
Descoberta de Drogas , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Proteínas , Ligantes , Descoberta de Drogas/métodos , Proteínas/química , Proteínas/metabolismo , Teoria Quântica
6.
Int J Biol Macromol ; 264(Pt 1): 130458, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38423421

RESUMO

The PD-1/PD-L1 protein-protein interaction (PPI) controls an adaptive immune resistance mechanism exerted by tumor cells to evade immune responses. The large-molecule nature of current commercial monoclonal antibodies against this PPI hampers their effectiveness by limiting tumor penetration and inducing severe immune-related side effects. Synthetic small-molecule inhibitors may overcome such limitations and have demonstrated promising clinical translation, but their design is challenging. Microbial natural products (NPs) are a source of small molecules with vast chemical diversity that have proved anti-tumoral activities, but which immunotherapeutic properties as PD-1/PD-L1 inhibitors had remained uncharacterized so far. Here, we have developed the first cell-based PD-1/PD-L1 blockade reporter assay to screen NPs libraries. In this study, 6000 microbial extracts of maximum biosynthetic diversity were screened. A secondary metabolite called alpha-cyclopiazonic acid (α-CPA) of a bioactive fungal extract was confirmed as a new PD-1/PD-L1 inhibitor with low micromolar range in the cellular assay and in an additional cell-free competitive assay. Thermal denaturation experiments with PD-1 confirmed that the mechanism of inhibition is based on its stabilization upon binding to α-CPA. The identification of α-CPA as a novel PD-1 stabilizer proves the unprecedented resolution of this methodology at capturing specific PD-1/PD-L1 PPI inhibitors from chemically diverse NP libraries.


Assuntos
Antígeno B7-H1 , Neoplasias , Humanos , Antígeno B7-H1/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Anticorpos Monoclonais
7.
J Med Chem ; 66(23): 15715-15727, 2023 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-38039505

RESUMO

Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2-FMN2 but not the Spire1-FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H-15N HSQC nuclear magnetic resonance. Extensive structure-activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2-FMN2 interaction.


Assuntos
Descoberta de Drogas , Simulação de Acoplamento Molecular , Ligantes
8.
Chembiochem ; 24(6): e202300006, 2023 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-36602436

RESUMO

Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.


Assuntos
Antineoplásicos , Proteína Supressora de Tumor p53 , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas c-mdm2 , Antineoplásicos/farmacologia , Imidazóis/farmacologia , Imidazóis/metabolismo , Linhagem Celular Tumoral , Apoptose
9.
Molecules ; 27(23)2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36500376

RESUMO

By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein.


Assuntos
Processamento Alternativo , Spliceossomos , Humanos , Spliceossomos/metabolismo , Ubiquitinas/genética , Espectroscopia de Ressonância Magnética , Computadores , Ligação Proteica , Ligantes , Sítios de Ligação
10.
ACS Chem Biol ; 17(9): 2655-2663, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36073782

RESUMO

Development of small molecules targeting the PD-L1/PD-1 interface is advancing both in industry and academia, but only a few have reached early-stage clinical trials. Here, we take a closer look at the general druggability of PD-L1 using in silico hot spot mapping and nuclear magnetic resonance (NMR)-based characterization. We found that the conformational elasticity of the PD-L1 surface strongly influences the formation of hot spots. We deconstructed several generations of known inhibitors into fragments and examined their binding properties using differential scanning fluorimetry (DSF) and protein-based nuclear magnetic resonance (NMR). These biophysical analyses showed that not all fragments bind to the PD-L1 ectodomain despite having the biphenyl scaffold. Although most of the binding fragments induced PD-L1 oligomerization, two compounds, TAH35 and TAH36, retain the monomeric state of proteins upon binding. Additionally, the presence of the entire ectodomain did not affect the binding of the hit compounds and dimerization of PD-L1. The data demonstrated here provide important information on the PD-L1 druggability and the structure-activity relationship of the biphenyl core moiety and therefore may aid in the design of novel inhibitors and focused fragment libraries for PD-L1.


Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Antígeno B7-H1/metabolismo , Compostos de Bifenilo , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química
11.
Int J Mol Sci ; 23(5)2022 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-35269760

RESUMO

Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b-2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.


Assuntos
Antineoplásicos , Neoplasias Hepáticas , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular , Linhagem Celular Tumoral , Glicólise , Hexoquinase/metabolismo , Neoplasias Hepáticas/tratamento farmacológico , Camundongos
12.
Sci Rep ; 12(1): 4682, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304498

RESUMO

Protein assembly plays an important role throughout all phyla of life, both physiologically and pathologically. In particular, aggregation and polymerization of proteins are key-strategies that regulate cellular function. In recent years, methods to experimentally study the assembly process on a single-molecule level have been developed. This progress concomitantly has triggered the question of how to analyze this type of single-filament data adequately and what experimental conditions are necessary to allow a meaningful interpretation of the analysis. Here, we developed two analysis methods for single-filament data: the visitation analysis and the average-rate analysis. We benchmarked and compared both approaches with the classic dwell-time-analysis frequently used to study microscopic association and dissociation rates. In particular, we tested the limitations of each analysis method along the lines of the signal-to-noise ratio, the sampling rate, and the labeling efficiency and bleaching rate of the fluorescent dyes used in single-molecule fluorescence experiments. Finally, we applied our newly developed methods to study the monomer assembly of actin at the single-molecule-level in the presence of the class II nucleator Cappuccino and the WH2 repeats of Spire. For Cappuccino, our data indicated fast elongation circumventing a nucleation phase whereas, for Spire, we found that the four WH2 motifs are not sufficient to promote de novo nucleation of actin.


Assuntos
Actinas , Proteínas dos Microfilamentos , Citoesqueleto de Actina/metabolismo , Actinas/genética , Actinas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Polimerização
13.
Int J Mol Sci ; 22(21)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34769226

RESUMO

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico , Peptidomiméticos , Animais , Antígeno B7-H1/metabolismo , Células CHO , Cricetulus , Avaliação de Medicamentos , Humanos , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/farmacologia , Células Jurkat , Peptidomiméticos/química , Peptidomiméticos/farmacologia
14.
Pharmaceuticals (Basel) ; 14(11)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34832861

RESUMO

The pharmacological effects of carbon to silicon bioisosteric replacements have been widely explored in drug design and medicinal chemistry. Here, we present a systematic investigation of the impact of different silyl groups on the anticancer activity of mucobromic acid (MBA) bearing furan-2(5H)-one core. We describe a comprehensive characterization of obtained compounds with respect to their anticancer potency and selectivity towards cancer cells. All four novel compounds exert stronger antiproliferative activity than MBA. Moreover, 3b induce apoptosis in colon cancer cell lines. A detailed investigation of the mechanism of action revealed that 3b activity stems from the down-regulation of survivin and the activation of caspase-3. Furthermore, compound 3b attenuates the clonogenic potential of HCT-116 cells. Interestingly, we also found that depending on the type of the silyl group, compound selectivity towards cancer cells could be precisely controlled. Collectively, we demonstrated the utility of silyl groups for adjusting both the potency and selectivity of silicon-containing compounds. These data reveal a link between the types of silyl group and compound potency, which could have bearings for the design of novel silicon-based anticancer drugs.

15.
J Med Chem ; 64(15): 11614-11636, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34313116

RESUMO

We describe a new class of potent PD-L1/PD-1 inhibitors based on a terphenyl scaffold that is derived from the rigidified biphenyl-inspired structure. Using in silico docking, we designed and then experimentally demonstrated the effectiveness of the terphenyl-based scaffolds in inhibiting PD-1/PD-L1 complex formation using various biophysical and biochemical techniques. We also present a high-resolution structure of the complex of PD-L1 with one of our most potent inhibitors to identify key PD-L1/inhibitor interactions at the molecular level. In addition, we show the efficacy of our most potent inhibitors in activating the antitumor response using primary human immune cells from healthy donors.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Compostos de Bifenilo/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antígeno B7-H1/metabolismo , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
16.
ACS Med Chem Lett ; 12(5): 768-773, 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34055224

RESUMO

The PD-1/PD-L1 axis has proven to be a highly efficacious target for cancer immune checkpoint therapy with several approved antibodies. Also, small molecules based on a biphenyl core can antagonize PD-1/PD-L1, leading to the in vitro formation of PD-L1 dimers. However, their development remains challenging, as we do not yet fully understand their mode of action. In this work, we designed a new scaffold based on our previously solved high-resolution structures of low-molecular-weight inhibitors bound to PD-L1. A small compound library was synthesized using the Groebke-Blackburn-Bienaymé multicomponent reaction (GBB-3CR), resulting in the structure-activity relationship of imidazo[1,2-a]pyridine-based inhibitors. These inhibitors were tested for their biological activity using various biophysical assays giving potent candidates with low-micromolar PD-L1 affinities. An obtained PD-L1 cocrystal structure reveals the binding to PD-L1. Our results open the door to an interesting bioactive scaffold that could lead to a new class of PD-L1 antagonists.

17.
Int J Mol Sci ; 22(4)2021 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-33672341

RESUMO

Accumulating evidence suggests that six proteases encoded in the spl operon of a dangerous human pathogen, Staphylococcus aureus, may play a role in virulence. Interestingly, SplA, B, D, and E have complementary substrate specificities while SplF remains to be characterized in this regard. Here, we describe the prerequisites of a heterologous expression system for active SplF protease and characterize the enzyme in terms of substrate specificity and its structural determinants. Substrate specificity of SplF is comprehensively profiled using combinatorial libraries of peptide substrates demonstrating strict preference for long aliphatic sidechains at the P1 subsite and significant selectivity for aromatic residues at P3. The crystal structure of SplF was provided at 1.7 Å resolution to define the structural basis of substrate specificity of SplF. The obtained results were compared and contrasted with the characteristics of other Spl proteases determined to date to conclude that the spl operon encodes a unique extracellular proteolytic system.


Assuntos
Peptídeo Hidrolases/química , Peptídeo Hidrolases/metabolismo , Staphylococcus aureus/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Cristalografia por Raios X , Escherichia coli/genética , Metionina/metabolismo , Modelos Moleculares , Peptídeo Hidrolases/genética , Peptídeos/química , Peptídeos/metabolismo , Especificidade por Substrato
18.
Structure ; 26(4): 572-579.e4, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29526434

RESUMO

Staphylococcus aureus is a dangerous human pathogen characterized by alarmingly increasing antibiotic resistance. Accumulating evidence suggests the role of Spl proteases in staphylococcal virulence. Spl proteases have restricted, non-overlapping substrate specificity, suggesting that they may constitute a first example of a proteolytic system in bacteria. SplA, SplB, and SplD were previously characterized in terms of substrate specificity and structural determinants thereof. Here we analyze the substrate specificity of SplE documenting its unique P1 preference among Spl proteases and, in fact, among all chymotrypsin-like (family S1) proteases characterized to date. This is interesting since our understanding of the general aspects of proteolysis is based on seminal studies of S1 family members. To better understand the molecular determinants of the unusual specificity of SplE, the crystal structure of the protein is determined here. Conclusions from structural analysis are evaluated by successful grafting of SplE specificity on the scaffold of SplB protease.


Assuntos
Proteínas de Bactérias/química , Peptídeos/química , Serina Proteases/química , Staphylococcus aureus/química , Fatores de Virulência/química , Sequência de Aminoácidos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Cinética , Modelos Moleculares , Mutação , Biblioteca de Peptídeos , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Serina Proteases/genética , Serina Proteases/metabolismo , Staphylococcus aureus/enzimologia , Staphylococcus aureus/patogenicidade , Especificidade por Substrato , Fatores de Virulência/genética , Fatores de Virulência/metabolismo
19.
Eur J Med Chem ; 150: 687-697, 2018 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-29571156

RESUMO

A series of 5-alkoxy derivatives of 3,4-dichloro-5-hydroxyfuran-2-(5H)-one (mucochloric acid, MCA) were obtained and subsequently subjected to modification in the C-4 position of 2(5H)-furanone ring. The cytotoxicity of newly synthesized compounds was evaluated in MTT assay against non-small cell lung cancer (A549) and healthy lung epithelial cell line (BEAS-2B). The derivatives containing a branched alkoxy substituent in the C-5 position demonstrated the highest anticancer properties, whereas modification of compounds in the C-4 position of 2(5H)-furanone ring only slightly improve their antiproliferative properties. Compounds 12 and 15 exhibited the best selectivity towards A549 cells and were also evaluated in a panel of cancer cell lines of different origin. Further investigation revealed that treatment of A549 cell line with compounds 12 and 15 led to G2 phase cell cycle arrest and induction of caspase-independent cell death. Moreover, compound 12 was found to act synergistically with erlotinib.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Furanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Humanos , Neoplasias Pulmonares/patologia , Estrutura Molecular , Relação Estrutura-Atividade
20.
Structure ; 23(12): 2341-2348, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26602187

RESUMO

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has recently provided breakthrough progress in the treatment of melanoma, non-small cell lung cancer, and other types of cancer. Small-molecule drugs interfering with this pathway are highly awaited, but their development is hindered by insufficient structural information. This study reveals the molecular details of the human PD-1/PD-L1 interaction based on an X-ray structure of the complex. First, it is shown that the ligand binding to human PD-1 is associated with significant plasticity within the receptor. Second, a detailed molecular map of the interaction surface is provided, allowing definition of the regions within both interacting partners that may likely be targeted by small molecules.


Assuntos
Antígeno B7-H1/química , Receptor de Morte Celular Programada 1/química , Sequência de Aminoácidos , Antígeno B7-H1/metabolismo , Sítios de Ligação , Humanos , Dados de Sequência Molecular , Receptor de Morte Celular Programada 1/metabolismo , Ligação Proteica
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