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1.
J Org Chem ; 89(7): 4760-4767, 2024 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-38544408

RESUMO

Although the construction of peptides with well-defined three-dimensional structures and predictable functions, including biological activity, using conformationally constrained ß-amino acids has been shown to be a very successful strategy, their broad application is limited by access to the appropriate building blocks. In particular, trans- and cis-stereoisomers of 2-aminocyclopentanecarboxylic acid (ACPC) are of high interest. The scalable synthesis of all four stereoisomers of Fmoc derivatives of ACPC is presented with NMR-based analysis methods for their enantiomeric purity.


Assuntos
Aminoácidos , Peptídeos , Estereoisomerismo , Peptídeos/química , Aminoácidos/química , Espectroscopia de Ressonância Magnética
2.
Mol Cancer ; 22(1): 150, 2023 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-37679783

RESUMO

Recent advances in immuno-oncology have opened up new and impressive treatment options for cancer. Notwithstanding, overcoming the limitations of the current FDA-approved therapies with monoclonal antibodies (mAbs) that block the PD-1/PD-L1 pathway continues to lead to the testing of multiple approaches and optimizations. Recently, a series of macrocyclic peptides have been developed that exhibit binding strengths to PD-L1 ranging from sub-micromolar to micromolar. In this study, we present the most potent non-antibody-based PD-1/PD-L1 interaction inhibitor reported to date. The structural and biological characterization of this macrocyclic PD-L1 targeting peptide provides the rationale for inhibition of both PD-1/PD-L1 and CD80/PD-L1 complexes. The IC50 and EC50 values obtained in PD-L1 binding assays indicate that the pAC65 peptide has potency equivalent to the current FDA-approved mAbs and may have similar activity to the BMS986189 peptide, which entered the clinical trial and has favorable safety and pharmacokinetic data. The data presented here delineate the generation of similar peptides with improved biological activities and applications not only in the field of cancer immunotherapy but also in other disorders related to the immune system.


Assuntos
Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Humanos , Anticorpos Monoclonais/farmacologia , Inibidores de Checkpoint Imunológico , Peptídeos/farmacologia
3.
Soft Matter ; 19(21): 3828-3840, 2023 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-37191235

RESUMO

In this paper, we show that a hierarchical approach for the construction of nanofibrils based on α,ß-peptide foldamers is a rational method for the design of novel self-assembled nanomaterials based on peptides. Incorporation of a trans-(1S,2S)-2-aminocyclopentanecarboxylic acid residue into the outer positions of the model coiled-coil peptide led to the formation of helical foldamers, which was determined by circular dichroism (CD) and vibrational spectroscopy. The oligomerization state of the obtained peptides in water was established by analytical ultracentrifugation (AUC). The thioflavin T assay and Congo red methods showed that the obtained α,ß-peptides possess a strong tendency to aggregate, leading to the formation of self-assembled nanostructures, which were assessed by microscopic techniques. The location of the ß-amino acid in the heptad repeat of the coiled-coil structure proved to have an influence on the secondary structure of the obtained peptides and on the morphology of the self-assembled nanostructures.


Assuntos
Nanoestruturas , Peptídeos , Sequência de Aminoácidos , Modelos Moleculares , Peptídeos/química , Estrutura Secundária de Proteína , Dicroísmo Circular
4.
J Enzyme Inhib Med Chem ; 38(1): 2244693, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37605435

RESUMO

The entry of the SARS-CoV-2 virus into a human host cell begins with the interaction between the viral spike protein (S protein) and human angiotensin-converting enzyme 2 (hACE2). Therefore, a possible strategy for the treatment of this infection is based on inhibiting the interaction of the two abovementioned proteins. Compounds that bind to the SARS-CoV-2 S protein at the interface with the alpha-1/alpha-2 helices of ACE2 PD Subdomain I are of particular interest. We present a stepwise optimisation of helical peptide foldamers containing trans-2-aminocylopentanecarboxylic acid residues as the folding-inducing unit. Four rounds of optimisation led to the discovery of an 18-amino-acid peptide with high affinity for the SARS-CoV-2 S protein (Kd = 650 nM) that inhibits this protein-protein interaction with IC50 = 1.3 µM. Circular dichroism and nuclear magnetic resonance studies indicated the helical conformation of this peptide in solution.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Humanos , Enzima de Conversão de Angiotensina 2 , SARS-CoV-2 , Peptídeos/farmacologia
5.
Chembiochem ; 23(4): e202100604, 2022 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-34856053

RESUMO

The ß-hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non-peptide structures for drug discovery. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well-defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid ß-hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary-structure propensity of the X residues. The high conformational stability of the scaffold results from tight contacts between cross-strand cationic and aromatic side chains, combined with the strong tendency of the d-Pro-l-Pro dipeptide to induce a type II' ß-turn. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non-ß-branched, poorly ß-sheet-prone residues at the X positions. Both the NMR and MD data confirm that our acyclic ß-hairpin scaffold is highly versatile as regards the amino-acid composition of the ß-sheet face opposite to the cationic-aromatic one.


Assuntos
Aminoácidos/química , Peptídeos/química , Modelos Moleculares , Conformação Proteica em Folha beta
6.
Chem Rec ; 22(8): e202200026, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35502852

RESUMO

Urease, an enzyme that catalyzes the hydrolysis of urea, is a virulence factor of various pathogenic bacteria. In particular, Helicobacter pylori, that colonizes the digestive tract and Proteus spp., that can infect the urinary tract, are related to urease activity. Therefore, urease inhibitors are considered as potential therapeutics against these infections. This review describes current knowledge of the structures, activity, and biological importance of bacterial ureases. Moreover, the structure-based design of several classes of bacterial urease inhibitors is presented and discussed. Phosphinic and phosphonic acids were applied as transition-state analogues, while Michael acceptors and ebselen derivatives were applied as covalent binders of cysteine residue. This review incorporates bacterial urease inhibitors from literature published between 2008 and 2021.


Assuntos
Helicobacter pylori , Urease , Inibidores Enzimáticos/farmacologia , Ureia/farmacologia , Urease/química
7.
Bioorg Med Chem Lett ; 71: 128806, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35660515

RESUMO

Miniproteins exhibit great potential as scaffolds for drug candidates because of their well-defined structure and good synthetic availability. Because of recently described methodologies for their de novo design, the field of miniproteins is emerging and can provide molecules that effectively bind to problematic targets, i.e., those that have been previously considered to be undruggable. This review describes methodologies for the development of miniprotein scaffolds and for the construction of biologically active miniproteins.


Assuntos
Química Farmacêutica , Engenharia de Proteínas , Engenharia de Proteínas/métodos
8.
Org Biomol Chem ; 19(19): 4272-4278, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34010377

RESUMO

The construction of ß-amino acid-containing peptides that fold to tertiary structures in solution remains challenging. Two model miniproteins, namely, Trp-cage and FSD, were scanned using a constrained ß-amino acid in order to evaluate its impact on the folding process. Relationships between forces stabilizing the miniprotein structure and conformational stability of analogues were found. The possibility of a significant increase of the conformational stability of the studied miniproteins by substitution with the ß-amino acid at the terminus of a helix is shown. On the basis of these results, ß-amino acid containing-peptide analogs with helical fragments substantially altered by the incorporation of several constrained ß-amino acids were designed, synthesized and evaluated with respect to their structure and stability. The smallest known ß-amino acid-containing peptide with a well-defined tertiary structure is described.


Assuntos
Peptídeos
10.
Bioorg Med Chem Lett ; 29(9): 1085-1089, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30850166

RESUMO

Targeted covalent inhibitors of urease were developed on the basis of the catechol structure. Forty amide and ester derivatives of 3,4-dihydroxyphenylacetic acid, caffeic acid, ferulic acid and gallic acid were obtained and screened against Sporosarcinia pasteurii urease. The most active compound, namely propargyl ester of 3,4-dihydroxyphenylacetic acid exhibited IC50 = 518 nM andkinact/Ki = 1379 M-1 s-1. Inhibitory activity of this compound was better and toxicity lower than those obtained for the starting compound - catechol. The molecular modelling studies revealed a mode of binding consistent with structure-activity relationships.


Assuntos
Antibacterianos/farmacologia , Catecóis/farmacologia , Sporosarcina/enzimologia , Urease/antagonistas & inibidores , Antibacterianos/química , Catecóis/química , Inibidores Enzimáticos/química , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação Proteica , Relação Estrutura-Atividade
11.
Bioorg Chem ; 81: 356-361, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30195249

RESUMO

De novo designed helix-loop-helix peptide foldamers containing cis-2-aminocyclopentanecarboxylic acid residues were evaluated for their conformational stability and possible use in enzyme mimetic development. The correlation between hydrogen bond network size and conformational stability was demonstrated through CD and NMR spectroscopies. Molecules incorporating a Cys/His/Glu triad exhibited enzyme-like hydrolytic activity.


Assuntos
Materiais Biomiméticos/química , Peptídeos/química , Sequência de Aminoácidos , Materiais Biomiméticos/síntese química , Catálise , Sequências Hélice-Alça-Hélice , Hidrolases/química , Hidrólise , Cinética , Peptídeos/síntese química , Engenharia de Proteínas , Desdobramento de Proteína
12.
Chemistry ; 23(60): 14980-14986, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28869688

RESUMO

Peptide foldamers have been studied for over two decades and numerous sequence patterns have been shown to form well-defined three-dimensional arrangements in solution. In particular, helices of various geometries have been described. In this article, different concepts concerning the construction of helical foldameric peptides, for which the possibility of governing the sense of the formed helix was evidenced, are presented and discussed.


Assuntos
Peptídeos/química , Engenharia de Proteínas , Sequência de Aminoácidos , Aminoácidos/química , Gramicidina/química , Gramicidina/metabolismo , Peptídeos/metabolismo , Estrutura Secundária de Proteína , Estereoisomerismo
13.
Bioorg Med Chem Lett ; 27(6): 1346-1350, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28236590

RESUMO

Covalent enzyme inhibitors constitute a highly important group of biologically active compounds, with numerous drugs available on the market. Although the discovery of inhibitors of urease, a urea hydrolyzing enzyme crucial for the survival of some human pathogens, is a field of medicinal chemistry that has grown in recent years, covalent urease inhibitors have been rarely investigated until now. Forty Michael acceptor-type compounds were screened for their inhibitory activities against bacterial urease, and several structures exhibited high potency in the nanomolar range. The correlation between chemical reactivity towards thiols and inhibitory potency indicated the most valuable compound - acetylenedicarboxylic acid, with Ki∗=42.5nM and logkGSH=-2.14. Molecular modelling studies revealed that acetylenedicarboxylic acid is the first example of highly effective mode of binding based on simultaneous bonding to a cysteine residue and interaction with nickel ions present in the active site. Activity-reactivity profiling of reversible covalent enzyme inhibitors is a general method for the identification of valuable drug candidates.


Assuntos
Bactérias/enzimologia , Inibidores Enzimáticos/farmacologia , Urease/antagonistas & inibidores , Células 3T3 , Animais , Inibidores Enzimáticos/química , Camundongos , Camundongos Endogâmicos BALB C , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 25(17): 4835-4844, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28778369

RESUMO

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile. Using the scaffold hopping approach, three structurally diverse heterocycles - 2,3-disubstituted imidazopyridines, 2,3-disubstituted benzimidazoles and 1,2,4-trisubstituted imidazoles emerged as promising antitubercular agents. All compounds were synthesized through easy and convenient methods and their structures confirmed by IR, 1H NMR, 13C NMR and MS. In-vitro cytotoxicity studies on normal kidney monkey cell lines and HepG2 cell lines, as well as metabolic stability studies on rat liver microsomes for some of the most active compounds, established that these compounds have negligible cytotoxicity and are metabolically stable. Interestingly the benzimidazole compound (4a) is as potent as the parent molecule BM212 (MIC 2.3µg/ml vs 0.7-1.5µg/ml), but is devoid of the toxicity against HepG2 cell lines (IC50 203.10µM vs 7.8µM).


Assuntos
Antituberculosos/química , Piperazinas/química , Pirróis/química , Animais , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/toxicidade , Linhagem Celular , Desenho de Fármacos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Piperazinas/toxicidade , Pirróis/farmacologia , Pirróis/toxicidade , Ratos , Relação Estrutura-Atividade
15.
Angew Chem Int Ed Engl ; 56(8): 2087-2091, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28079284

RESUMO

Peptide foldamers containing both cis-ß-aminocyclopentanecarboxylic acid and α-amino acid residues combined in various sequence patterns (ααß, αααß, αßααß, and ααßαααß) were screened using CD and NMR spectroscopy for the tendency to form helices. ααß-Peptides were found to fold into an unprecedented and well-defined 16/17/15/18/14/17-helix. By extending the length of the sequence or shifting a fragment of the sequence from one terminus to another in ααß-peptides, the balance between left-handed and right-handed helix populations present in the solution can be controlled. Engineering of the peptide sequence could lead to compounds with either a strong propensity for the selected helix sense or a mixture of helical conformations of opposite senses.


Assuntos
Peptídeos/química , Dobramento de Proteína , Sequência de Aminoácidos , Aminoácidos/química , Dicroísmo Circular , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Estrutura Secundária de Proteína
16.
Angew Chem Int Ed Engl ; 56(44): 13732-13735, 2017 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-28881104

RESUMO

Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Antígeno B7-H1/imunologia , Descoberta de Drogas , Humanos , Células Jurkat , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Simulação de Acoplamento Molecular , Receptor de Morte Celular Programada 1/imunologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Linfócitos T/imunologia
17.
Bioorg Med Chem Lett ; 26(3): 707-713, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26764190

RESUMO

Protein-protein interactions (PPIs) are key elements of several important biological processes and have emerged as valuable targets in medicinal chemistry. Importantly, numerous specific protein-protein interactions (e.g., p53-HDM2 and Bcl-2-BH3 domains) were found to be involved in the development of several diseases, including various types of cancer. In general, the discovery of new synthetic PPI inhibitors is a challenging task because protein surfaces have not evolved in a manner that allows for specific binding of low molecular weight compounds. Here, we review the discovery strategies for peptide-based PPI inhibitors. Although peptide-based drug candidates exhibit significant drawbacks (in particular, low proteolytic stability), modifications of either the side chains or backbone could provide molecules of interest. Moreover, due to the large molecular size of peptide-based compounds, the discovery of molecules that specifically interact with extended protein surfaces is possible. Two major strategies for constructing peptide-based PPI inhibitors are as follows: (a) cyclization (e.g., stapled peptides) and (b) modification of the backbone structure (e.g., ß-peptides and peptoids). These approaches for constructing PPI inhibitors enhance both the inhibitory activity and pharmacokinetic properties compared with non-modified α-peptides.


Assuntos
Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos Cíclicos/química , Peptídeos Cíclicos/metabolismo , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteína Supressora de Tumor p53/antagonistas & inibidores
18.
J Enzyme Inhib Med Chem ; 31(6): 931-8, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26235917

RESUMO

Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-H-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from Mycobacterium tuberculosis. Most of the studied compounds exhibited activities in micromolar range, with N-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, N-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and N-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound - L-methionine-S-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis.


Assuntos
Antituberculosos/farmacologia , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutamato-Amônia Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/enzimologia , Antituberculosos/síntese química , Antituberculosos/química , Difosfonatos/síntese química , Difosfonatos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutamato-Amônia Ligase/metabolismo , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Chirality ; 27(10): 752-60, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26415853

RESUMO

Because of their unique 3D arrangement, naturally occurring Cinchona alkaloids and their synthetic derivatives have found wide-ranging applications in chiral recognition. Recently, we determined the enantioselective properties of C-9-phosphate mixed triesters of quinine as versatile chiral solvating agents in nuclear magnetic resonance (NMR) spectroscopy. In the current study, we introduce new zwitterionic members of this class of molecules containing a negatively charged phosphate moiety (i.e., ethyl, n-butyl and phenyl hydrogen quininyl phosphate). An efficient approach for synthesizing these compounds is elaborated, and full characterization, including conformational and autoaggregation phenomena studies, was performed. Therefore, their ability to induce NMR anisochrony of selected enantiomeric substrates (i.e., primarily N-DNB-protected amino acids and their methyl esters) was analyzed compared to uncharged diphenyl quininyl phosphate and its positively charged quaternary ammonium hydrochloride salt. In addition, (1) H and (13) C NMR experiments revealed their enantiodiscrimination potential toward novel analytes, such as secondary amines and nonprotected amino acids.

20.
J Med Chem ; 67(5): 3205-3231, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38394369

RESUMO

Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific antiviral drugs in a well-established and efficient manner is crucial. Taking into account the strong ability of viruses to change, therapies with diversified molecular targets must be sought. In addition to the widely explored viral enzyme inhibitor approach, inhibition of protein-protein interactions is a very valuable strategy. In this Perspective, protein-protein interaction inhibitors targeting HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses are reviewed and discussed. Antibodies, peptides/peptidomimetics, and small molecules constitute three classes of compounds that have been explored, and each of them has some advantages and disadvantages for drug development.


Assuntos
Vírus Chikungunya , Doença pelo Vírus Ebola , Vírus , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Inibidores Enzimáticos , Doença pelo Vírus Ebola/tratamento farmacológico
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