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Self-assembling choline mimicks with enhanced binding affinities to C-LytA protein.

Shi Y, Zhou H, Zhang X, Wang J, Long J, Yang Z, Ding D - Sci Rep (2014)

Bottom Line: In this work, we successfully developed two self-assembling choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK', which have the abilities to self-assemble into nanoparticles and nanofibers, respectively, yielding multivalent architectures.The self-assembling Ada-GFFYKKK' and Nap-GFFYKKK' show strong interactions with C-LytA, which possess much higher association constant values to the choline-binding modules as compared to the individual peptide Fmoc-K'.This study thus provides a self-assembly approach to yield inhibitors that are very promising for reducing the pneumococcal virulence.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, P. R. China.

ABSTRACT
Streptococcus pneumoniae (pneumococcus) causes multiple illnesses in humans. Exploration of effective inhibitors with multivalent attachment sites for choline-binding modules is of great importance to reduce the pneumococcal virulence. In this work, we successfully developed two self-assembling choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK', which have the abilities to self-assemble into nanoparticles and nanofibers, respectively, yielding multivalent architectures. Additionally, the best characterized choline-binding module, C-terminal moiety of the pneumococcal cell-wall amidase LytA (C-LytA) was also produced with high purity. The self-assembling Ada-GFFYKKK' and Nap-GFFYKKK' show strong interactions with C-LytA, which possess much higher association constant values to the choline-binding modules as compared to the individual peptide Fmoc-K'. This study thus provides a self-assembly approach to yield inhibitors that are very promising for reducing the pneumococcal virulence.

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Chemical structures of choline mimicks with possible self-assembling properties.
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f1: Chemical structures of choline mimicks with possible self-assembling properties.

Mentions: Recently, great interest has been focused on utilizing self-assembly rather than covalent scaffold synthesis to achieve multivalency, as the self-assembly approach has several advantages, such as simplified synthetic procedures, ease of incorporating multiple active units, tunability of nanostructure morphology as well as its characteristic responsive nature1718192021. In this contribution, we designed and synthesized two choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK' (1 and 2 in Fig. 1, respectively), which can self-assemble into nanostructures with multivalent K' groups. K' is a derivative of K by its quaternization. Due to the similar chemical structure of K' to choline, we expected that the multivalent K' groups might efficiently match the tandem choline-binding repeats in C-LytA. The isothermal titration calorimetry (ITC) results revealed that both self-assembling 1 and 2 exhibited far higher association constant with C-LytA as compared to Fmoc-K' itself. To the best of our knowledge, this is the first report on using K' to replace choline for preparation of inhibitors that could specifically and very tightly bind to choline-binding modules. Furthermore, most of the currently available inhibitors were based on covalent scaffolds; rather limited work has focused on the exploration of inhibitors using the self-assembly approach. This study thus provides fundamental guidelines to yield new pneumococcal inhibitors by self-assembly, which will inspire more exciting work in this research field.


Self-assembling choline mimicks with enhanced binding affinities to C-LytA protein.

Shi Y, Zhou H, Zhang X, Wang J, Long J, Yang Z, Ding D - Sci Rep (2014)

Chemical structures of choline mimicks with possible self-assembling properties.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4197414&req=5

f1: Chemical structures of choline mimicks with possible self-assembling properties.
Mentions: Recently, great interest has been focused on utilizing self-assembly rather than covalent scaffold synthesis to achieve multivalency, as the self-assembly approach has several advantages, such as simplified synthetic procedures, ease of incorporating multiple active units, tunability of nanostructure morphology as well as its characteristic responsive nature1718192021. In this contribution, we designed and synthesized two choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK' (1 and 2 in Fig. 1, respectively), which can self-assemble into nanostructures with multivalent K' groups. K' is a derivative of K by its quaternization. Due to the similar chemical structure of K' to choline, we expected that the multivalent K' groups might efficiently match the tandem choline-binding repeats in C-LytA. The isothermal titration calorimetry (ITC) results revealed that both self-assembling 1 and 2 exhibited far higher association constant with C-LytA as compared to Fmoc-K' itself. To the best of our knowledge, this is the first report on using K' to replace choline for preparation of inhibitors that could specifically and very tightly bind to choline-binding modules. Furthermore, most of the currently available inhibitors were based on covalent scaffolds; rather limited work has focused on the exploration of inhibitors using the self-assembly approach. This study thus provides fundamental guidelines to yield new pneumococcal inhibitors by self-assembly, which will inspire more exciting work in this research field.

Bottom Line: In this work, we successfully developed two self-assembling choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK', which have the abilities to self-assemble into nanoparticles and nanofibers, respectively, yielding multivalent architectures.The self-assembling Ada-GFFYKKK' and Nap-GFFYKKK' show strong interactions with C-LytA, which possess much higher association constant values to the choline-binding modules as compared to the individual peptide Fmoc-K'.This study thus provides a self-assembly approach to yield inhibitors that are very promising for reducing the pneumococcal virulence.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, P. R. China.

ABSTRACT
Streptococcus pneumoniae (pneumococcus) causes multiple illnesses in humans. Exploration of effective inhibitors with multivalent attachment sites for choline-binding modules is of great importance to reduce the pneumococcal virulence. In this work, we successfully developed two self-assembling choline mimicks, Ada-GFFYKKK' and Nap-GFFYKKK', which have the abilities to self-assemble into nanoparticles and nanofibers, respectively, yielding multivalent architectures. Additionally, the best characterized choline-binding module, C-terminal moiety of the pneumococcal cell-wall amidase LytA (C-LytA) was also produced with high purity. The self-assembling Ada-GFFYKKK' and Nap-GFFYKKK' show strong interactions with C-LytA, which possess much higher association constant values to the choline-binding modules as compared to the individual peptide Fmoc-K'. This study thus provides a self-assembly approach to yield inhibitors that are very promising for reducing the pneumococcal virulence.

Show MeSH
Related in: MedlinePlus