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Multivariate design and evaluation of a set of RGRPQ-derived innate immunity peptides
Umeå University, Faculty of Medicine, Odontology.
Umeå University, Faculty of Science and Technology, Chemistry.
Umeå University, Faculty of Medicine, Odontology, Cariology.
Umeå University, Faculty of Science and Technology, Chemistry.
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2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 22, 15164-15171 p.Article in journal (Refereed) Published
Abstract [en]

Oral commensal Streptococcus gordonii proteolytically cleave the salivary PRP-1 polypeptide into an RGRPQ innate peptide. The Arg and Gln termini are crucial for RGRPQ-mediated ammonia production and proliferation by S. gordonii SK12 and adhesion inhibition and desorption by Actinomyces naeslundii T14V, respectively. Here we have applied (i) a multivariate approach using RGRPQ-related peptides varied at amino acids 2, 3, and 4 simultaneously and (ii) size and N- and C-terminal modifications of RGRPQ to generate structure activity information. While the N-terminal arginine motif mediated ammonia production independent of peptide size, other responses required more or less full-length peptide motifs. The motifs for adhesion inhibition and desorption were the same. The adhesion and proliferation motifs required similarly a hydrophobic/low polarity amino acid 4 but differentially a hydrophilic or hydrophobic character of amino acids 2/3, respectively; polar peptides with small/hydrophilic and hydrophilic amino acids 2 and 3, respectively, had high adhesion inhibition/desorption activity, and lipophilic peptides with large/hydrophobic amino acids 2 and 3 had high proliferation activity. Accordingly, while RIWWQ had increased proliferation but abolished adhesion/desorption activity, peptides designed with hydrophilic amino acids 2 and 3 were predicted to behave in the opposite way. Moreover, a RGRPQ mimetic for all three responses should mimic small hydrophilic, large nitrogen-containing, and hydrophobic/low polarity amino acids 2, 3, and 4, respectively. Peptides fulfilling these criteria were 1-1.6-fold improved in all three responses. Thus, both mimetics and peptides with differential proliferation and adhesion activities may be generated for evaluation in biofilm models.

Place, publisher, year, edition, pages
2006. Vol. 281, no 22, 15164-15171 p.
Keyword [en]
Actinomyces/immunology/pathogenicity, Amino Acid Sequence, Ammonia/metabolism, Bacterial Adhesion/drug effects, Drug Design, Humans, Immunity; Natural, Oligopeptides/chemistry/*immunology/pharmacology, Peptide Library, Peptides/chemistry/immunology, Quantitative Structure-Activity Relationship, Saliva/immunology, Salivary Proteins/chemistry/immunology, Streptococcus/immunology/pathogenicity
URN: urn:nbn:se:umu:diva-10654DOI: doi:10.1074/jbc.M511727200PubMedID: 16595685OAI: diva2:150325
Kemi, kemometri, odontologi, kariologiAvailable from: 2007-04-19 Created: 2007-04-19 Last updated: 2009-10-01Bibliographically approved
In thesis
1. Adhesion-related interactions of Actinomyces and Streptococcus biofilm bacteria
Open this publication in new window or tab >>Adhesion-related interactions of Actinomyces and Streptococcus biofilm bacteria
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adhesion of bacteria is a key event in biofilm formation and is mediated by bacterial adhesins recognising host or bacterial partner receptors. In oral biofilm formation, primary Actinomyces and Streptococcus colonizers adhere to salivary pellicle proteins such as proline-rich proteins (PRPs) as well as to mucosal surfaces. Subsequently, Actinomyces and Streptococcus strains and other bacteria, such as Veillonella, Fusobacterium and Porphyromonas, adhere to each other. The nature of this community is highly important for the health or disease status, although specific pathogenic species may also have been implicated.

The aim of this thesis was to study key players in early oral colonisation, Actinomyces and Streptococcus species, and more specifically the nature of their adhesins and ligands. A further aim was to study the function of the salivary PRP proteins and an innate peptide derived thereof on bacterial adhesion, proliferation and regulation of pH, i.e. key factors in biofilm formation.

In paper I and II, adhesion, proliferation and pH affecting features of the RGRPQ (arginine-glycine-arginine-proline-glutamine) peptide, derived from PRP-1, were demonstrated. By use of an alanine-scan (I), motifs for adhesion inhibition and desorption of Actinomyces naeslundii, and proliferation stimulation, ammonia production and inhibition of sucrose induced pH drop by Streptococcus gordonii were indicated. The RGRPQ peptide also stimulated S. gordonii colonisation in vivo. In paper II, a more sophisticated quantitative structure-activity relationship (QSAR) study, using statistical molecular design (SMD) and multivariate modelling (partial least squares projections to latent structures, PLS), further narrowed down the RGRPQ peptide motifs. The R and Q amino acids were crucial for activity. For proliferation a hydrophobic and large size third position amino acid was crucial, while adhesion inhibition and desorption needed a small hydrophilic second position amino acid. All functions depended on a low polarity hydrophobic fourth position. Accordingly, activities could be optimized separately, with decreased function in the others.

In paper III and IV, focus was on the bacterial adhesins and their binding epitopes. The genes for FimA major subunit proteins of type-2 fimbriae were sequenced from A. naeslundii genospecies 1 and 2 and Actinomyces odontolyticus, each with unique carbohydrate binding specificities (III). Three major subtypes of FimA proteins were found that correlated with binding specificity, including a novel fimA gene in A. odontolyticus. All subtypes contained a pilin, LPXTG and E box motif. In paper IV, multiple PRP binding patterns for Actinomyces and Streptococcus strains were mapped using a hybrid peptide construct. The two most deviating binding groups deviated in type-1 fimbriae mediated binding to milk and saliva protein ligands.

In conclusion, differences in bacterial adhesins and their ability to utilise salivary proteins may render bacteria tropism for different niches. Peptides derived from protein receptors, such as RGRPQ, may be important modulators of biofilm formation, giving commensal bacteria a competitive edge in the bacterial community.

Place, publisher, year, edition, pages
Umeå: Odontologi, 2006. 45 p.
Umeå University odontological dissertations, ISSN 0345-7532 ; 92
biofilm, Actinomyces, Streptococcus, adhesion
National Category
urn:nbn:se:umu:diva-860 (URN)91-7264-111-8 (ISBN)
Public defence
2006-09-29, Sal B, Tandläkarhögskolan 9 tr, 90187 Umeå, Umeå, 13:00 (English)
Available from: 2006-09-08 Created: 2006-09-08 Last updated: 2009-10-01Bibliographically approved

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