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1.
J Am Chem Soc ; 137(10): 3616-21, 2015 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-25742366

RESUMO

The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min(-1) M(-1) k(inact)/K(I) values and ≥10-fold selectivity for PAD3 over PADs 1, 2, and 4.


Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidrolases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Humanos , Hidantoínas/química , Hidantoínas/farmacologia , Isoenzimas/antagonistas & inibidores , Desiminases de Arginina em Proteínas , Especificidade por Substrato
2.
J Am Chem Soc ; 133(39): 15559-67, 2011 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-21861531

RESUMO

Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and, consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homo-oligomers by X-ray crystallography, NMR spectroscopy, and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 Å. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide K(cis/trans) values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homo-oligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.


Assuntos
Desenho de Fármacos , Glicinas N-Substituídas/química , Peptídeos/química , Peptoides/química , Cristalografia por Raios X , Modelos Moleculares , Peptoides/síntese química , Dobramento de Proteína , Multimerização Proteica , Estabilidade Proteica , Estrutura Secundária de Proteína , Estereoisomerismo
3.
J Org Chem ; 75(18): 6068-78, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-20722367

RESUMO

The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the ω, ϕ, and ψ dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n→π*(C═O) interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turnlike and beyond, and will facilitate the continued development of well-folded peptoids.


Assuntos
Amidas/química , Peptoides/química , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , Estrutura Molecular , Peptoides/síntese química , Estereoisomerismo
4.
J Med Chem ; 63(22): 13796-13824, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33170686

RESUMO

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein-protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/metabolismo , Inibidores de PCSK9 , Pró-Proteína Convertase 9/metabolismo , RNA Mensageiro/metabolismo , Animais , Células Cultivadas , Cristalografia por Raios X/métodos , Inibidores Enzimáticos/química , Feminino , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Proteína Convertase 9/química , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , RNA Mensageiro/química , Ratos , Ratos Wistar , Relação Estrutura-Atividade
5.
J Am Chem Soc ; 131(45): 16555-67, 2009 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-19860427

RESUMO

Controlling the equilibria between backbone cis- and trans-amides in peptoids, or N-substituted glycine oligomers, constitutes a significant challenge in the construction of discretely folded peptoid structures. Through the analysis of a set of monomeric peptoid model systems, we have developed new and general strategies for controlling peptoid conformation that utilize local noncovalent interactions to regulate backbone amide rotameric equilibria, including n-->pi*, steric, and hydrogen bonding interactions. The chemical functionalities required to implement these strategies are typically confined to the peptoid side chains, preserve chirality at the side chain N-alpha-carbon known to engender peptoid structure, and are fully compatible with standard peptoid synthesis techniques. Our examinations of peptoid model systems have also elucidated how solvents affect various side chain-backbone interactions, revealing fundamental aspects of these noncovalent interactions in peptoids that were largely uncharacterized previously. As validation of our monomeric model systems, we extended the scope of this study to include peptoid oligomers and have now demonstrated the importance of local steric and n-->pi* interactions in dictating the structures of larger, folded peptoids. This new, modular design strategy has guided the construction of peptoids containing 1-naphthylethyl side chains, which we show can be utilized to effectively eliminate trans-amide rotamers from the peptoid backbone, yielding the most conformationally homogeneous class of peptoid structures yet reported in terms of amide rotamerism. Overall, this research has afforded a valuable and expansive set of design tools for the construction of both discretely folded peptoids and structurally biased peptoid libraries and should shape our understanding of peptoid folding.


Assuntos
Peptoides/química , Dobramento de Proteína , Amidas/química , Modelos Moleculares , Peptoides/síntese química , Conformação Proteica , Estereoisomerismo
6.
Chem Biol ; 14(4): 351-7, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17462570

RESUMO

There is an urgent, global need for the development of new antibacterial agents. We have applied the small-molecule macroarray approach to the synthesis and screening of antibacterial compounds active against the Gram-positive pathogen Staphylococcus aureus. Several macroarrays of 1,3-diphenyl-2-propen-1-ones (chalcones), cyanopyridines, and pyrimidines were synthesized on a planar cellulose support system on the order of days. This support system was found to be highly compatible with antibacterial assay formats, including disk-diffusion and agar-overlay visualization methods. Further, sufficient compound was isolated from each spot of the macroarray for both compound characterization and minimum inhibitory concentration (MIC) estimation. Analysis of the small-molecule macroarrays in these assays uncovered a set of antibacterial agents with in vitro MIC values against methicillin-resistant S. aureus comparable to certain antibacterial drugs in use today.


Assuntos
Antibacterianos/isolamento & purificação , Química Farmacêutica , Desenho de Fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/farmacologia , Chalconas/síntese química , Chalconas/isolamento & purificação , Chalconas/farmacologia , Farmacorresistência Bacteriana , Resistência a Meticilina , Testes de Sensibilidade Microbiana/métodos , Piridinas/síntese química , Piridinas/isolamento & purificação , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/isolamento & purificação , Pirimidinas/farmacologia
7.
ACS Comb Sci ; 13(2): 175-80, 2011 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-21210707

RESUMO

Bacterial resistance to current antibiotics is a major global health threat. Consequently, there is an urgent need for the identification of new antibacterial agents. We are applying the small-molecule macroarray platform to rapidly synthesize and screen compounds for activity against methicillin-resistant Staphylococcus aureus (MRSA). Herein, we report the synthesis of a 1,3-diphenyl-2-propen-1-one (chalcone) macroarray using a Rink-amide linker-derivatized cellulose support. The Rink linker allowed for the incorporation of a broader array of library building blocks relative to our previous syntheses because milder reaction conditions could be utilized; significantly higher compound loadings were also achieved (~80% vs ~15%). Analysis of the 174-member chalcone macroarray in off-support antibacterial screening assays revealed three chalcones with minimum inhibitory concentration (MIC) values against MRSA comparable to currently used antibacterial drugs and low hemolytic activities. These results serve to further showcase and extend the utility of the small molecule macroarray for antibacterial discovery.


Assuntos
Antibacterianos/síntese química , Chalconas/síntese química , Staphylococcus aureus Resistente à Meticilina , Análise em Microsséries , Antibacterianos/química , Antibacterianos/farmacologia , Chalconas/química , Chalconas/farmacologia , Técnicas de Química Combinatória/métodos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Fatores de Tempo
8.
Biopolymers ; 96(5): 604-16, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22180908

RESUMO

N-hydroxy amides can be found in many naturally occurring and synthetic compounds and are known to act as both strong proton donors and chelators of metal cations. We have initiated studies of peptoids, or N-substituted glycines which contain N-hydroxy amide side chains to investigate the potential effects of these functional groups on peptoid backbone amide rotamer equilibria and local conformations. We reasoned that the propensity of these functional groups to participate in hydrogen bonding could be exploited to enforce intramolecular or intermolecular interactions that yield new peptoid structures. Here, we report the design, synthesis, and detailed conformational analysis of a series of model N-hydroxy peptoids. These peptoids were readily synthesized, and their structures were analyzed in solution by 1D and 2D NMR and in the solid-state by X-ray crystallography. The N-hydroxy amides were found to strongly favor trans conformations with respect to the peptoid backbone in chloroform. More notably, unique sheet-like structures held together via intermolecular hydrogen bonds were observed in the X-ray crystal structures of an N-hydroxy amide peptoid dimer, which to our knowledge represent the first structure of this type reported for peptoids. These results suggest that the N-hydroxy amide can be utilized to control both local backbone geometries and longer-range intermolecular interactions in peptoids, and represents a new functional group in the peptoid design toolbox.


Assuntos
Amidas/química , Desenho de Fármacos , Peptoides/síntese química , Acilação , Amidas/síntese química , Cristalografia por Raios X , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Peptoides/química , Estrutura Secundária de Proteína
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