RESUMO
Trichothecenes are toxins produced by certain species from several fungal genera, including Aspergillus, Fusarium, Isaria, Paramyrothecium, Stachybotrys, Trichoderma, and Trichothecium. These toxins are of interest because they contribute to the toxigenicity, plant pathogenicity, and/or biological control activities of some fungi. All trichothecenes have the same core (12,13-epoxytrichothec-9-ene or EPT) structure but can differ from one another by the presence or absence of a macrocyclic ring formed from polyketide and isoprenoid substituents esterified to carbon atoms 4 and 15 of EPT, respectively. Genes required for formation and some modifications of EPT have been elucidated, but almost nothing is known about genes specific to the formation of the macrocyclic ring. Therefore, we used genomic, transcriptomic, metabolomic, and gene deletion analyses to identify genes that are required specifically for the formation of the macrocyclic ring. These analyses identified one gene, TRI24, that is predicted to encode an acyltransferase and that is required for macrocyclic ring formation during biosynthesis of macrocyclic trichothecenes by the fungus Paramyrothecium roridum. In addition, a TRI24 deletion mutant of P. roridum caused less severe disease symptoms on common bean and had less antifungal activity than its wild-type progenitor strain. We propose that the reduced aggressiveness and antifungal activity of the mutant resulted from its inability to produce trichothecenes with a macrocyclic ring. To our knowledge, this is the first report of a gene required specifically for the formation of the macrocyclic ring of trichothecenes and that loss of the macrocyclic ring of trichothecenes can alter the biological activities of a fungus. KEY POINTS: ⢠TRI24 gene is found in all known macrocyclic trichothecene-producing fungi. ⢠A tri24-deletion mutant exhibits a reduction in antifungal and plant disease activities. ⢠TRI24 is the first described gene specific to macrocyclic trichothecene biosynthesis.
Assuntos
Tricotecenos , Tricotecenos/metabolismo , Tricotecenos/química , Doenças das Plantas/microbiologia , Deleção de Genes , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Metabolômica , Genes Fúngicos , Perfilação da Expressão GênicaRESUMO
Macrocycles are one of nature's preferred choices to generate large but cell-permeable bioactive molecules. Macrocyclization is increasingly prominent in medicinal chemistry beyond natural products, especially for difficult-to-drug targets. However, strategies to best exploit the potential of macrocycles are only beginning to emerge. Here we survey drug discovery campaigns from the past decade that cumulated in advanced macrocyclic drug-like compounds or drug candidates. Most macrocycles were conceived by ring closing based on U- or C-shaped bioactive conformations observed in co-crystal structures. We focus on the key step from linear precursors to the first macrocycle and the follow-up optimization of the resulting macrocyclic scaffold. Conformational control recurrently emerged as a key factor for macrocycle properties and linkers as an opportunity for optimization. With increasingly challenging drug targets, we expect these trends to become more prominent and relevant.
Assuntos
Descoberta de Drogas , Compostos Macrocíclicos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Ciclização , Humanos , Conformação MolecularRESUMO
Interactions between proteins and α-helical peptides have been the focus of drug discovery campaigns. However, the large interfaces formed between multiple turns of an α-helix and a binding protein represent a significant challenge to inhibitor discovery. Modified peptides featuring helix-stabilizing macrocycles have shown promise as inhibitors of these interactions. Here, we tested the ability of N-terminal to side-chain thioether-cyclized peptides to inhibit the α-helix binding protein Mcl-1, by screening a trillion-scale library. The enriched peptides were lariats featuring a small, four-amino-acid N-terminal macrocycle followed by a short linear sequence that resembled the natural α-helical Mcl-1 ligands. These "Heliats" (helical lariats) bound Mcl-1 with tens of nM affinity, and inhibited the interaction between Mcl-1 and a natural peptide ligand. Macrocyclization was found to stabilize α-helical structures and significantly contribute to affinity and potency. Yet, the 2nd and 3rd positions within the macrocycle were permissible to sequence variation, so that a minimal macrocyclic motif, of an N-acetylated d-phenylalanine at the 1st position thioether connected to a cysteine at the 4th, could be grafted into a range of peptides and stabilize helical conformations. We found that d-stereochemistry is more helix-stabilizing than l- at the 1st position in the motif, as the d-amino acid can utilize polyproline II torsional angles that allow for more optimal intrachain hydrogen bonding. This mixed stereochemistry macrocyclic N-cap is synthetically accessible, requiring only minor modifications to standard solid-phase peptide synthesis, and its compatibility with peptide screening can provide ready access to helix-focused peptide libraries for de novo inhibitor discovery.
Assuntos
Compostos Macrocíclicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Peptídeos , Estereoisomerismo , Peptídeos/química , Peptídeos/síntese química , Peptídeos/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/química , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Humanos , Conformação Proteica em alfa-Hélice , Modelos MolecularesRESUMO
Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.
Assuntos
Desenho de Fármacos , Compostos Macrocíclicos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Humanos , Estrutura Molecular , AnimaisRESUMO
Macrocyclic peptides are promising scaffolds for the covalent ligand discovery. However, platforms enabling the direct identification of covalent macrocyclic ligands in a high-throughput manner are limited. In this study, we present an mRNA display platform allowing selection of covalent macrocyclic inhibitors using 1,3-dibromoacetone-vinyl sulfone (DBA-VS). Testcase selections on TEV protease resulted in potent covalent inhibitors with diverse cyclic structures, among which cTEV6-2, a macrocyclic peptide with a unique C-terminal cyclization, emerged as the most potent covalent inhibitor of TEV protease described to-date. This study outlines the workflow for integrating chemical functionalizationâinstallation of a covalent warheadâwith mRNA display and showcases its application in targeted covalent ligand discovery.
Assuntos
RNA Mensageiro , RNA Mensageiro/antagonistas & inibidores , Ciclização , Sulfetos/química , Sulfetos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Sulfonas/química , Sulfonas/farmacologia , Descoberta de Drogas , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Estrutura MolecularRESUMO
The coronavirus disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spread worldwide for more than 3 years. Although the hospitalization rate and mortality have decreased dramatically due to wide vaccination effort and improved treatment options, the disease is still a global health issue due to constant viral mutations, causing negative impact on social and economic activities. In addition, long COVID and complications arising from COVID-19 weeks after infection have become a concern for public health experts. Therefore, better treatments for COVID-19 are still needed. Herein, we describe a class of macrocyclic peptidomimetic compounds that are potent inhibitors of SARS-Cov-2 3CL protease (3CLpro). Significantly, some of the compounds showed a higher stability against human liver microsomes (HLM t1/2 > 180 min) and may be suitable for oral administration without the need for a pharmacokinetic (PK) boosting agent such as ritonavir.
Assuntos
Antivirais , Proteases 3C de Coronavírus , Compostos Macrocíclicos , SARS-CoV-2 , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Humanos , SARS-CoV-2/efeitos dos fármacos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacocinética , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Antivirais/farmacocinética , Microssomos Hepáticos/metabolismo , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/síntese química , Descoberta de Drogas , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacocinética , Relação Estrutura-AtividadeRESUMO
Ten macrocyclic peptides, each comprising 14 amino acids, were designed and synthesized based on the Tau aggregation model hexapeptides AcPHF6* and AcPHF6. The design took into account the aggregation tendencies of each residue in AcPHF6* and AcPHF6, their aggregation models, while employing peptide-based structural design principles including N-methylation to promote turns and to block hydrogen bond propagation and elongation of the aggregation chain. NMR analysis supported that all these peptides adopted an antiparallel ß-sheet conformation. Self-aggregation studies characterized the aggregation properties of these peptides, identifying two peptides with the highest (P3) and lowest (P8) aggregation tendencies. In cross-aggregation studies with the parent peptides AcPHF6* and AcPHF6, P3 and P8 were found to promote and reduce aggregation, respectively. Furthermore, P3 and P8 demonstrated an enhancement and diminution effect on the aggregation of K18wt, indicating their capacity to modulate aggregation even at the macromolecular level. Thus, the two simple peptides, P3 and P8 selectively exhibit pro- or anti-aggregation effects on PHF peptides and Tau. This study, has thus developed structurally well-defined non-complex peptides, derived from AcPHF6* and AcPHF6, to modulate Tau aggregation as desired, offering applications in Tau model studies and the development of Tau aggregation inhibitors or promoters.
Assuntos
Agregados Proteicos , Proteínas tau , Proteínas tau/metabolismo , Proteínas tau/química , Proteínas tau/antagonistas & inibidores , Agregados Proteicos/efeitos dos fármacos , Humanos , Estrutura Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Oligopeptídeos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Relação Dose-Resposta a DrogaRESUMO
Macrocyclization of acyclic compounds is a powerful strategy for improving inhibitor potency and selectivity. Here we have optimized 2-aminopyrimidine-based macrocycles to use these compounds as chemical tools for the ephrin kinase family. Starting with a promiscuous macrocyclic inhibitor, 6, we performed a structure-guided activity relationship and selectivity study using a panel of over 100 kinases. The crystal structure of EPHA2 in complex with the developed macrocycle 23 provided a basis for further optimization by specifically targeting the back pocket, resulting in compound 55, a potent inhibitor of EPHA2/A4 and GAK. Subsequent front-pocket derivatization resulted in an interesting in cellulo selectivity profile, favoring EPHA4 over the other ephrin receptor kinase family members. The dual EPHA2/A4 and GAK inhibitor 55 prevented dengue virus infection of Huh7 liver cells. However, further investigations are needed to determine whether this was a compound-specific effect or target-related.
Assuntos
Inibidores de Proteínas Quinases , Pirimidinas , Receptor EphA2 , Humanos , Linhagem Celular Tumoral , Cristalografia por Raios X , Vírus da Dengue/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Receptor EphA2/antagonistas & inibidores , Receptor EphA2/metabolismo , Relação Estrutura-Atividade , MorfolinasRESUMO
Prenylation of peptides is widely observed in the secondary metabolites of diverse organisms, granting peptides unique chemical properties distinct from proteinogenic amino acids. Discovery of prenylated peptide agents has largely relied on isolation or genome mining of naturally occurring molecules. To devise a platform technology for de novo discovery of artificial prenylated peptides targeting a protein of choice, here we have integrated the thioether-macrocyclic peptide (teMP) library construction/selection technology, so-called RaPID (Random nonstandard Peptides Integrated Discovery) system, with a Trp-C3-prenyltransferase KgpF involved in the biosynthesis of a prenylated natural product. This unique enzyme exhibited remarkably broad substrate tolerance, capable of modifying various Trp-containing teMPs to install a prenylated residue with tricyclic constrained structure. We constructed a vast library of prenylated teMPs and subjected it to in vitro selection against a phosphoglycerate mutase. This selection platform has led to the identification of a pseudo-natural prenylated teMP inhibiting the target enzyme with an IC50 of 30â nM. Importantly, the prenylation was essential for the inhibitory activity, enhanced serum stability, and cellular uptake of the peptide, highlighting the benefits of peptide prenylation. This work showcases the de novo discovery platform for pseudo-natural prenylated peptides, which is readily applicable to other drug targets.
Assuntos
Prenilação , Ligantes , Humanos , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/metabolismo , Dimetilaliltranstransferase/metabolismo , Dimetilaliltranstransferase/química , Dimetilaliltranstransferase/antagonistas & inibidores , Prenilação de ProteínaRESUMO
Cobalt(III) compounds with tetradentate ligands have been widely employed to deliver cytotoxic and imaging agents into cells. A large body of work has focused on using cobalt(III)-cyclam scaffolds for this purpose. Here, we investigate the cytotoxic properties of cobalt(III) complexes containing 14-membered macrocycles related to cyclam. A breast cancer stem cell (CSC) in vitro model was used to gauge efficacy. Specifically, [Co(1,4,7,11-tetraazacyclotetradecane)Cl2]+ (1) and [Co(1-oxa-4,8,12-triazacyclotetradecane)Cl2]+ (2) were synthesised and characterised, and their breast CSC activity was determined. The cobalt(III) complexes 1 and 2 displayed micromolar potency towards bulk breast cancer cells and breast CSCs grown in monolayers. Notably, 1 and 2 displayed selective potency towards breast CSCs over bulk breast cancer cells (up to 4.5-fold), which was similar to salinomycin (an established breast CSC-selective agent). The cobalt(III) complexes 1 and 2 were also able to inhibit mammosphere formation at low micromolar doses (with respect to size and number). The mammopshere inhibitory effect of 2 was similar to that of salinomycin. Our studies show that cobalt(III) complexes with 1,4,7,11-tetraazacyclotetradecane and 1-oxa-4,8,12-triazacyclotetradecane macrocycles could be useful starting points for the development of new cobalt-based delivery systems that can transport cytotoxic and imaging agents into breast CSCs.
Assuntos
Antineoplásicos , Cobalto , Células-Tronco Neoplásicas , Humanos , Cobalto/química , Células-Tronco Neoplásicas/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Linhagem Celular Tumoral , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Sobrevivência Celular/efeitos dos fármacosRESUMO
Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 107 M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.
Assuntos
Compostos Macrocíclicos , Animais , Camundongos , Humanos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Agregação Eritrocítica/efeitos dos fármacos , Ácidos Sulfônicos/química , Ácidos Sulfônicos/farmacologiaRESUMO
Nonproteinogenic amino acids, including d-α-, ß-, and γ-amino acids, present in bioactive peptides play pivotal roles in their biochemical activities and proteolytic stabilities. d-α-Amino acids (dαAA) are widely used building blocks that can enhance the proteolytic stability. Cyclic ß2,3-amino acids (cßAA), for instance, can fold peptides into rigid secondary structures, improving the binding affinity and proteolytic stability. Cyclic γ2,4-amino acids (cγAA) are recently highlighted as rigid residues capable of preventing the proteolysis of flanking residues. Simultaneous incorporation of all dαAA, cßAA, and cγAA into a peptide is expected to yield l-α/d-α/ß/γ-hybrid peptides with improved stability and potency. Despite challenges in the ribosomal incorporation of multiple nonproteinogenic amino acids, our engineered tRNAPro1E2 successfully reaches such a difficulty. Here, we report the ribosomal synthesis of macrocyclic l-α/d-α/ß/γ-hybrid peptide libraries and their application to in vitro selection against interferon gamma receptor 1 (IFNGR1). One of the resulting l-α/d-α/ß/γ-hybrid peptides, IB1, exhibited remarkable inhibitory activity against the IFN-γ/IFNGR1 protein-protein interaction (PPI) (IC50 = 12 nM), primarily attributed to the presence of a cßAA in the sequence. Additionally, cγAAs and dαAAs in the resulting peptides contributed to their serum stability. Furthermore, our peptides effectively inhibit IFN-γ/IFNGR1 PPI at the cellular level (best IC50 = 0.75 µM). Altogether, our platform expands the chemical space available for exploring peptides with high activity and stability, thereby enhancing their potential for drug discovery.
Assuntos
Receptor de Interferon gama , Interferon gama , Receptores de Interferon , Interferon gama/metabolismo , Receptores de Interferon/metabolismo , Receptores de Interferon/química , Humanos , Ligação Proteica , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/metabolismoRESUMO
Macrocyclic peptides possess unique features, making them highly promising as a drug modality. However, evaluating their bioactivity through wet lab experiments is generally resource-intensive and time-consuming. Despite advancements in artificial intelligence (AI) for bioactivity prediction, challenges remain due to limited data availability and the interpretability issues in deep learning models, often leading to less-than-ideal predictions. To address these challenges, we developed PepExplainer, an explainable graph neural network based on substructure mask explanation (SME). This model excels at deciphering amino acid substructures, translating macrocyclic peptides into detailed molecular graphs at the atomic level, and efficiently handling non-canonical amino acids and complex macrocyclic peptide structures. PepExplainer's effectiveness is enhanced by utilizing the correlation between peptide enrichment data from selection-based focused library and bioactivity data, and employing transfer learning to improve bioactivity predictions of macrocyclic peptides against IL-17C/IL-17 RE interaction. Additionally, PepExplainer underwent further validation for bioactivity prediction using an additional set of thirteen newly synthesized macrocyclic peptides. Moreover, it enabled the optimization of the IC50 of a macrocyclic peptide, reducing it from 15 nM to 5.6 nM based on the contribution score provided by PepExplainer. This achievement underscores PepExplainer's skill in deciphering complex molecular patterns, highlighting its potential to accelerate the discovery and optimization of macrocyclic peptides.
Assuntos
Aprendizado Profundo , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Estrutura Molecular , Humanos , Peptídeos/química , Peptídeos/farmacologia , Relação Estrutura-Atividade , Relação Dose-Resposta a DrogaRESUMO
There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.
Assuntos
Antivirais , Vírus Lassa , Compostos Macrocíclicos , Replicação Viral , Vírus Lassa/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Replicação Viral/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química , Humanos , Animais , Chlorocebus aethiops , Células Vero , Febre Lassa/virologia , Febre Lassa/tratamento farmacológico , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Proteínas Virais/genéticaRESUMO
Three new series of macrocyclic active site-directed inhibitors of the Zika virus (ZIKV) NS2B-NS3 protease were synthesized. First, attempts were made to replace the basic P3 lysine residue of our previously described inhibitors with uncharged and more hydrophobic residues. This provided numerous compounds with inhibition constants between 30 and 50 nM. A stronger reduction of the inhibitory potency was observed when the P2 lysine was replaced by neutral residues, all of these inhibitors possess Ki values >1 µM. However, it is possible to replace the P2 lysine with the less basic 3-aminomethylphenylalanine, which provides a similarly potent inhibitor of the ZIKV protease (Ki = 2.69 nM). Crystal structure investigations showed that the P2 benzylamine structure forms comparable interactions with the protease as lysine. Twelve additional structures of these inhibitors in complex with the protease were determined, which explain many, but not all, SAR data obtained in this study. All individual modifications in the P2 or P3 position resulted in inhibitors with low antiviral efficacy in cell culture. Therefore, a third inhibitor series with combined modifications was synthesized; all of them contain a more hydrophobic d-cyclohexylalanine in the linker segment. At a concentration of 40 µM, two of these compounds possess similar antiviral potency as ribavirin at 100 µM. Due to their reliable crystallization in complex with the ZIKV protease, these cyclic compounds are very well suited for a rational structure-based development of improved inhibitors.
Assuntos
Antivirais , Compostos Macrocíclicos , Zika virus , Zika virus/enzimologia , Zika virus/efeitos dos fármacos , Relação Estrutura-Atividade , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Estrutura Molecular , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Relação Dose-Resposta a Droga , Serina Endopeptidases/metabolismo , Humanos , Inibidores de Protease Viral/farmacologia , Inibidores de Protease Viral/síntese química , Inibidores de Protease Viral/química , Cristalografia por Raios X , Proteases Virais , Nucleosídeo-Trifosfatase , RNA Helicases DEAD-boxRESUMO
Access to 1,2,3-triazolium-grafted peptoid macrocycles was developed by macrocyclization and multivalent postmodification of linear peptoid oligomers carrying an alternance of benzylic and propargyl groups as side chains. X-ray analysis and NMR studies revealed a conformational preference for constrained hairpin-shaped structures leading to the facial amphipathic character of these macrocycles. A preliminary evaluation showed the antimicrobial activities of these new cationic amphipathic architectures.
Assuntos
Antibacterianos , Compostos Macrocíclicos , Testes de Sensibilidade Microbiana , Peptidomiméticos , Triazóis , Triazóis/química , Triazóis/farmacologia , Estrutura Molecular , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptidomiméticos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Cristalografia por Raios X , Bactérias/efeitos dos fármacosRESUMO
Macrocycles are defined as cyclic compounds with 12 or more members. In medicinal chemistry, they are categorized based on their core chemistry into cyclic peptides and macrocycles. Macrocycles are advantageous because of their structural diversity and ability to achieve high affinity and selectivity towards challenging targets that are often not addressable by conventional small molecules. The potential of macrocyclization to optimize drug-like properties while maintaining adequate bioavailability and permeability has been emphasized as a key innovation in medicinal chemistry. This review provides a detailed case study of the application of macrocyclization over the past 5 years, starting from the initial analysis of acyclic active compounds to optimization of the resulting macrocycles for improved efficacy and drug-like properties. Additionally, it illustrates the strategic value of macrocyclization in contemporary drug discovery efforts.
Assuntos
Química Farmacêutica , Compostos Macrocíclicos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Humanos , Ciclização , Descoberta de Drogas , Estrutura MolecularRESUMO
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
Assuntos
Antivirais , Linfócitos T CD8-Positivos , Carbamatos , Hepacivirus , Hepatite C Crônica , Receptor de Morte Celular Programada 1 , Sulfonamidas , Linfócitos T Reguladores , Humanos , Antivirais/uso terapêutico , Masculino , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/genética , Feminino , Pessoa de Meia-Idade , Carbamatos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Hepatite C Crônica/sangue , Ciclopropanos/uso terapêutico , Valina/análogos & derivados , Prolina/análogos & derivados , Anilidas/uso terapêutico , Anilidas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Compostos Macrocíclicos/farmacologia , Idoso , Ritonavir/uso terapêutico , Adulto , Quimioterapia Combinada , Linfócitos T Auxiliares-Indutores/imunologia , Imidazóis , Isoquinolinas , PirrolidinasRESUMO
Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.
Assuntos
Antivirais , Vírus da Influenza A Subtipo H1N1 , Compostos Macrocíclicos , Oximas , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Oximas/farmacologia , Oximas/química , Oximas/síntese química , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Relação Estrutura-Atividade , Humanos , Cães , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química , Compostos Macrocíclicos/síntese química , Animais , Células Madin Darby de Rim Canino , Descoberta de Drogas , Biomimética , Oseltamivir/farmacologia , Oseltamivir/químicaRESUMO
Given the crucial role of the main protease (Mpro) in the replication cycle of SARS-CoV-2, this viral cysteine protease constitutes a high-profile drug target. We investigated peptidomimetic azapeptide nitriles as auspicious, irreversibly acting inhibitors of Mpro. Our systematic approach combined an Mpro active-site scanning by combinatorially assembled azanitriles with structure-based design. Encouraged by the bioactive conformation of open-chain inhibitors, we conceptualized the novel chemotype of macrocyclic azanitriles whose binding mode was elucidated by cocrystallization. This strategy provided a favorable entropic contribution to target binding and resulted in the development of the extraordinarily potent Mpro inhibitor 84 with an IC50 value of 3.23 nM and a second-order rate constant of inactivation, kinac/Ki, of 448,000 M-1s-1. The open-chain Mpro inhibitor 58, along with the macrocyclic compounds 83 and 84, a broad-spectrum anticoronaviral agent, demonstrated the highest antiviral activity with EC50 values in the single-digit micromolar range. Our findings are expected to promote the future development of peptidomimetic Mpro inhibitors as anti-SARS-CoV-2 agents.