Using Fluorous Amino Acids to Modulate the Biological Activity of an Antimicrobial Peptide

Gottler, Lindsey M.; Lee, Hyang Yeol; Shelburne, Charles E.; Ramamoorthy, Ayyalusamy; Marsh, E. Neil G.

doi:10.1002/cbic.200700643

Cited by 90 publications

(80 citation statements)

References 33 publications

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“…Proteins with sequences containing up to ∼25% fluorous residues have been synthesized without gross structural perturbation. In almost all cases, fluorination significantly enhances stability to thermal unfolding, chemical denaturation, and proteolytic degradation, with minimal impact on the biological activity of the protein or peptide (18,(21)(22)(23)(24).…”

mentioning

confidence: 99%

Structural basis for the enhanced stability of highly fluorinated proteins

Buer¹,

Meagher

Stuckey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Noncanonical amino acids have proved extremely useful for modifying the properties of proteins. Among them, extensively fluorinated (fluorous) amino acids seem particularly effective in increasing protein stability; however, in the absence of structural data, the basis of this stabilizing effect remains poorly understood. To address this problem, we solved X-ray structures for three small proteins with hydrophobic cores that are packed with either fluorocarbon or hydrocarbon side chains and compared their stabilities. Although larger, the fluorinated residues are accommodated within the protein with minimal structural perturbation, because they closely match the shape of the hydrocarbon side chains that they replace. Thus, stability increases seem to be better explained by increases in buried hydrophobic surface area that accompany fluorination than by specific fluorous interactions between fluorinated side chains. This finding is illustrated by the design of a highly fluorinated protein that, by compensating for the larger volume and surface area of the fluorinated side chains, exhibits similar stability to its nonfluorinated counterpart. These structure-based observations should inform efforts to rationally modulate protein function using noncanonical amino acids.de novo-designed proteins | protein structure | coiled-coil proteins | unnatural amino acids | hexafluoroleucine

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confidence: 99%

Structural basis for the enhanced stability of highly fluorinated proteins

Buer¹,

Meagher

Stuckey

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…While natural AMPs may be brominated or occasionally chlorinated, chemists prefer fluorinated amino acids to improve stability of synthetic peptides [58,59]. The enhanced peptide stability may result from increase in size or hydrophobicity due to fluorination [60,61]. Incorporation of D-amino acids provides another useful approach for improvement of peptide stability.…”

Section: Modifications Of Linear Peptide Templatesmentioning

confidence: 99%

Post-Translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering

Wang¹

2011

CBIOT

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Natural antimicrobial peptides (AMPs) are gene-coded defense molecules discovered in all the three life domains: Eubacteria, Archaea, and Eukarya. The latter covers protists, fungi, plants, and animals. It is now recognized that amino acid composition, peptide sequence, and posttranslational modifications determine to a large extent the structure and function of AMPs. This article systematically describes post-translational modifications of natural AMPs annotated in the antimicrobial peptide database (http://aps.unmc.edu/AP). Currently, 1147 out of 1755 AMPs in the database are modified and classified into more than 17 types. Through chemical modifications, the peptides fold into a variety of structural scaffolds that target bacterial surfaces or molecules within cells. Chemical modifications also confer desired functions to a particular peptide. Meanwhile, these modifications modulate other peptide properties such as stability. Elucidation of the relationship between AMP property and chemical modification inspires peptide engineering. Depending on the objective of our design, peptides may be modified in various ways so that the desired features can be enhanced whereas unwanted properties can be minimized. Therefore, peptide design plays an essential role in developing natural AMPs into a new generation of therapeutic molecules.

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“…But fluorinated compounds are rare in nature [2] due to the properties of fluoride, its high redox potential, and its propensity to be hydrated [3,4]. Nevertheless, the characteristic fluorinated derivatives in nature, such as metabolic intermediates, have been proved extremely useful in medicine and agriculture, and the categories of fluorinated compounds used in these areas are ever increasing [5]. Some clinical drugs such as fluconazole, voriconazole, and itraconazole are all fluorine including triazole, presently playing a leading role in the treatment of invasive fungal infections [6].…”

Section: Introductionmentioning

confidence: 98%

Spectroscopic Studies on the Interaction of Fluorine Containing Triazole with Bovine Serum Albumin

Liu

Mei

Zhang

et al. 2010

Biol Trace Elem Res

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The binding of one fluorine including triazole (C(10)H(9)FN(4)S, FTZ) to bovine serum albumin (BSA) was studied by spectroscopic techniques including fluorescence spectroscopy, UV-Vis absorption, and circular dichroism (CD) spectroscopy under simulative physiological conditions. Fluorescence data revealed that the fluorescence quenching of BSA by FTZ was the result of forming a complex of BSA-FTZ, and the binding constants (K (a)) at three different temperatures (298, 304, and 310 K) were 1.516 × 10(4), 1.627 × 10(4), and 1.711 × 10(4) mol L(-1), respectively, according to the modified Stern-Volmer equation. The thermodynamic parameters ΔH and ΔS were estimated to be 7.752 kJ mol(-1) and 125.217 J mol(-1) K(-1), respectively, indicating that hydrophobic interaction played a major role in stabilizing the BSA-FTZ complex. It was observed that site I was the main binding site for FTZ to BSA from the competitive experiments. The distance r between donor (BSA) and acceptor (FTZ) was calculated to be 7.42 nm based on the Förster theory of non-radioactive energy transfer. Furthermore, the analysis of fluorescence data and CD data revealed that the conformation of BSA changed upon the interaction with FTZ.

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Using Fluorous Amino Acids to Modulate the Biological Activity of an Antimicrobial Peptide

Cited by 90 publications

References 33 publications

Structural basis for the enhanced stability of highly fluorinated proteins

Structural basis for the enhanced stability of highly fluorinated proteins

Post-Translational Modifications of Natural Antimicrobial Peptides and Strategies for Peptide Engineering

Spectroscopic Studies on the Interaction of Fluorine Containing Triazole with Bovine Serum Albumin

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