Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Seo, Jiwon; Martásek, Pavel; Roman, Linda J.; Silverman, Richard B.

doi:10.1016/j.bmc.2007.01.001

Cited by 23 publications

(16 citation statements)

References 29 publications

(9 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…N-acetyl-hydroxysuccinimide (NHS-Ac) was synthesized according to established methods [27] using commercially available materials without any further processing. N,N=-dicyclohexylcarbodiimide (7.64 g, 37.0 mmol) (Sigma-Aldrich, St. Louis, MO) was slowly added to a stirred room-temperature solution containing glacial acetic acid (1.9 mL, 33.2 mmol) (Fisher, Fairlawn, NJ) and N-hydroxysuccinimide (3.80 g, 33.0 mmol) (Sigma-Aldrich, St. Louis, MO) dissolved in dichloromethane (33 mL) (Fisher, Fairlawn, NJ).…”

Section: Methodsmentioning

confidence: 99%

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Chen

Schuster

Sfyroera

et al. 2008

J. Am. Soc. Mass Spectrom.

View full text Add to dashboard Cite

The extracellular fibrinogen-binding protein (Efb), an immunosuppressive and anti-inflammatory protein secreted by Staphylococcus aureus, has been identified as a potent inhibitor of complement-mediated innate immunity. Efb functions by binding to and disrupting the function of complement component 3 (C3). In a recent study, we presented a high-resolution co-crystal structure of the complement inhibitory domain of Efb (Efb-C) bound to its cognate domain (C3d) from human C3 and employed a series of structure/function analyses that provided evidence for an entirely new, conformational change-based mechanism of complement inhibition. To better understand the Efb/C3 complex and its downstream effects on C3 inhibition, we investigated the solvent-accessibility and protein interface of Efb(-C)/C3d using a method of lysine acetylation, proteolytic digestion, and mass spectrometric analysis. Lysine modification in Efb was monitored by the mass increment of lysine-containing fragments. Besides confirming the binding sites observed in co-crystal structure study, the in-solution data presented here suggest additional contacting point(s) between the proteins that were not revealed by crystallography. The results of this study demonstrate that solution-based analysis of protein-protein interactions can provide important complementary information on the nature of protein-protein interactions. (J Am Soc Mass Spectrom 2008, 19, 55-65)

show abstract

Section: Methodsmentioning

confidence: 99%

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Chen

Schuster

Sfyroera

et al. 2008

J. Am. Soc. Mass Spectrom.

View full text Add to dashboard Cite

show abstract

“…Nonetheless, despite their activities, these nitroarginine-based dipeptide inhibitors also have many drawbacks. Concerns over the multiple charges of the molecules, the low likelihood of oral bioavailability, and the lability of the peptide bond promoted modifications such as amide-bond reduction, 94 conformational restriction, 95,96 and introduction of lipophilic groups, 97 which gave rise to a variety of increasingly potent and selective peptidic and peptidomimetic inhibitors, such as 9 , 10 , and 11 . The high activity of these inhibitors was still a result, in part, of the presence of their basic side chains.…”

Section: Inhibition Of Neuronal Nitric Oxide Synthasementioning

confidence: 99%

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

et al. 2014

Self Cite

View full text Add to dashboard Cite

Nitric oxide (NO) is an important signaling molecule in the human body, playing a crucial role in cell and neuronal communication, regulation of blood pressure, and in immune activation. However, overproduction of NO by the neuronal isoform of nitric oxide synthase (nNOS)is one of the fundamental causes underlying neurodegenerative disorders and neuropathic pain. Therefore, developing small molecules for selective inhibition of nNOS over related isoforms(eNOS and iNOS) is therapeutically desirable. The aims of this review focus on the regulation and dysregulation of NO signaling, the role of NO in neurodegeneration and pain, the structure and mechanism of nNOS, and the use of this information to design selective inhibitors of this enzyme. Structure-based drug design, the bioavailability and pharmacokinetics of these inhibitors, and extensive target validation through animal studies are addressed.

show abstract

“…Hence, inhibition of NOS to decrease NO biosynthesis has been an attractive approach for the design of potential new drugs for diseases caused by NO overproduction [7], [8], [9], and [10]. Many NOS inhibitors have been developed and tested based on an in vitro assay using recombinant enzymes [8], [10], [11], [12], [13], and [14]. An in vitro assay is important for initial inhibitor screening and for enzyme mechanism studies.…”

Section: Introductionmentioning

confidence: 99%

A cellular model for screening neuronal nitric oxide synthase inhibitors

Fang

Silverman

2009

Analytical Biochemistry

Self Cite

View full text Add to dashboard Cite

Nitric oxide synthase (NOS) inhibitors are potential drug candidates because it has been well demonstrated that excessive production of NO critically contributes to a range of diseases. Most inhibitors have been screened in vitro using recombinant enzymes, leading to the discovery of a variety of potent compounds. To make inhibition studies more physiologically relevant and bridge the gap between the in vitro assay and in vivo studies, we report here a cellular model for screening NOS inhibitors. Stable transformants were generated by overexpressing rat neuronal NOS in HEK 293T cells. The enzyme was activated by introducing calcium into cells, and its activity was assayed by determining the amount of nitrite that was formed in culture media using the Griess reagent. We tested a few NOS inhibitors with this assay and found that the method is sensitive, versatile, and easy to use. The cell-based assay provides more information than in vitro assays regarding the bioavailability of NOS inhibitors, and it is suitable for high-throughput screening.

show abstract

Selective l-nitroargininylaminopyrrolidine and l-nitroargininylaminopiperidine neuronal nitric oxide synthase inhibitors

Cited by 23 publications

References 29 publications

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Solution insights into the structure of the Efb/C3 complement inhibitory complex as revealed by lysine acetylation and mass spectrometry

Development of nitric oxide synthase inhibitors for neurodegeneration and neuropathic pain

A cellular model for screening neuronal nitric oxide synthase inhibitors

Contact Info

Product

Resources

About