A novel class of enkephalinase inhibitors containing a C-terminal sulfo group

Mimura, Tetsutaro; Nakamura, Yasuhisa; Nishino, Junko; Sawayama, Tadahiro; Komiya, Toshio; Deguchi, Takashi; Kita, Atsuko; Nakamura, Hideo; Matsumoto, Junichi

doi:10.1021/jm00081a024

Cited by 12 publications

(9 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the observation that both wild-type enzyme and N542G mutant are inhibited by S448 with similar IC50 values is consistent with our hypothesis that the NH proton of the P2' residue interacts with Asn542. All these results are consistent with the findings of other authors who observed that the replacement of the hydrogen from the NH group of the P2' residue by a methyl or cyclopropyl group produced a dramatic loss of inhibitor binding [51][52][53][54][55].…”

Section: Discussionsupporting

confidence: 93%

Evidence that Asn542 of neprilysin (EC 3.4.24.11) is involved in binding of the P2′ residue of substrates and inhibitors

Dion

Moual

Fournié‐Zaluski

et al. 1995

Biochemical Journal

View full text Add to dashboard Cite

Neprilysin (EC 3.4.24.11) is a Zn2+ metallopeptidase involved in the degradation of biologically active peptides, e.g. enkephalins and atrial natriuretic peptide. The substrate specificity and catalytic activity of neprilysin resemble those of thermolysin, a crystallized bacterial Zn2+ metalloprotease. Despite little overall homology between the primary structures of thermolysin and neprilysin, many of the amino acid residues involved in catalysis, as well as Zn2+ and substrate binding, are highly conserved. Most of the active-site residues of neprilysin have their homologues in thermolysin and have been characterized by site-directed mutagenesis. Furthermore, hydrophobic cluster analysis has revealed some other analogies between the neprilysin and thermolysin sequences [Benchetrit, Bissery, Mornon, Devault, Crine and Roques (1988) Biochemistry 27, 592-596]. According to this analysis the role of Asn542 in the neprilysin active site is analogous to that of Asn112 of thermolysin, which is to bind the substrate. Site-directed mutagenesis was used to change Asn542 to Gly or Gln residues. The effect of these mutations on substrate catalysis and inhibitor binding was examined with a series of thiorphan-like compounds containing various degrees of methylation at the P2' residue. For both mutated enzymes, determination of kinetic parameters with [D-Ala2,Leu5]enkephalin as substrate showed that the large decrease in activity was attributable to an increase in Km (14-16-fold) whereas kcat values were only slightly affected (2-3-fold decrease). This is in agreement with Asn542 being involved in substrate binding rather than directly in catalysis. Finally, the IC50 values for thiorphan and substituted thiorphans strongly suggest that Asn542 of neprilysin binds the substrate on the amino side of the P2' residue by formation of a unique hydrogen bond.

show abstract

Section: Discussionsupporting

confidence: 93%

Evidence that Asn542 of neprilysin (EC 3.4.24.11) is involved in binding of the P2′ residue of substrates and inhibitors

Dion

Moual

Fournié‐Zaluski

et al. 1995

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…General Procedure for the Synthesis of 2-Alkylacrylic Acids ( 4a − f ) . 2-Alkylacrylic acids 4a − f were prepared from dimethyl malonate according to a literature procedure ( − ). Dimethyl malonate (44 mmol) and sodium methoxide (88 mmol) in methanol (100 mL) were refluxed for 20 min and the proper alkyl iodide (30 mmol) in methanol (50 mL) was added.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Antibacterial Activity of Peptide Deformylase Inhibitors

et al. 2000

View full text Add to dashboard Cite

Peptide deformylase catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential character in bacterial cells makes it an attractive target for antibacterial drug design. In this work, we have rationally designed and synthesized a series of peptide thiols that act as potent, reversible inhibitors of purified recombinant peptide deformylase from Escherichia coli and Bacillus subtilis. The most potent inhibitor has a K(I) value of 11 nM toward the B. subtilis enzyme. These inhibitors showed antibacterial activity against both Gram-positive and Gram-negative bacteria, with minimal inhibitory concentrations (MIC) as low as 5 microM ( approximately 2 microg/mL). The PDF inhibitors induce bacterial cell lysis and are bactericidal toward all four bacterial strains that have been tested, B. subtilis, Staphylococcus epidermidis, Enterococcus faecalis, and E. coli. Resistance evaluation of one of the inhibitors (1b) against B. subtilis showed that no resistant clone could be found from >1 x 10(9) cells. Quantitative analysis using a set of inhibitors designed to possess varying potencies against the deformylase enzyme revealed a linear correlation between the MIC values and the K(I) values. These results suggest that peptide deformylase is the likely molecular target responsible for the antibacterial activity of these inhibitors and is therefore a viable target for antibacterial drug design.

show abstract

“…Starting from these considerations, the aim was to fight the appearance of the "stress"-related expression of microcontractions and wrinkles. Unfortunately, enkephalins exhibit a very short lifetime (about 20 seconds), because the enkephalinase enzymes rapidly destroy them [122]. Thus, intending to extend the lifetime of enkephalins, NUXE performed a screening of 165,000 plants, identifying those containing a sufficient amount of pentagalloyl glucose (PGG)-the molecule able to inhibit the activity of enkephalinases [123][124][125].…”

Section: Discovering Neurocosmetic Ingredients From Plant Extractsmentioning

confidence: 99%

Neurocosmetics in Skincare—The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation

et al. 2021

View full text Add to dashboard Cite

The “modern” cosmetology industry is focusing on research devoted to discovering novel neurocosmetic functional ingredients that could improve the interactions between the skin and the nervous system. Many cosmetic companies have started to formulate neurocosmetic products that exhibit their activity on the cutaneous nervous system by affecting the skin’s neuromediators through different mechanisms of action. This review aims to clarify the definition of neurocosmetics, and to describe the features of some functional ingredients and products available on the market, with a look at the regulatory aspect. The attention is devoted to neurocosmetic ingredients for combating skin stress, explaining the stress pathways, which are also correlated with skin aging. “Neuro-relaxing” anti-aging ingredients derived from plant extracts and neurocosmetic strategies to combat inflammatory responses related to skin stress are presented. Afterwards, the molecular basis of sensitive skin and the suitable neurocosmetic ingredients to improve this problem are discussed. With the aim of presenting the major application of Botox-like ingredients as the first neurocosmetics on the market, skin aging is also introduced, and its theory is presented. To confirm the efficacy of the cosmetic products on the market, the concept of cosmetic claims is discussed.

show abstract

A novel class of enkephalinase inhibitors containing a C-terminal sulfo group

Cited by 12 publications

References 1 publication

Evidence that Asn542 of neprilysin (EC 3.4.24.11) is involved in binding of the P2′ residue of substrates and inhibitors

Evidence that Asn542 of neprilysin (EC 3.4.24.11) is involved in binding of the P2′ residue of substrates and inhibitors

Synthesis and Antibacterial Activity of Peptide Deformylase Inhibitors

Neurocosmetics in Skincare—The Fascinating World of Skin–Brain Connection: A Review to Explore Ingredients, Commercial Products for Skin Aging, and Cosmetic Regulation

Contact Info

Product

Resources

About