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J. Biol. Chem., Vol. 281, Issue 22, 15164-15171, June 2, 2006

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Multivariate Design and Evaluation of a Set of RGRPQ-derived Innate Immunity Peptides^*

Mirva Drobni, Ing-Marie Olsson, Christer Eriksson, Fredrik Almqvist, and Nicklas Strömberg¹

From the Department of Odontology/Cariology and Department of Chemistry/Organic Chemistry, UmeÅ University, SE-901 87 UmeÅ, Sweden

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 similarily 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.

Received for publication, October 31, 2005 , and in revised form, March 15, 2006.

^* This work was supported by grants from the Swedish Research Council (Projects 10906, 3532, 10832, and K5104-20005891), the Swedish Cancer Society (Project 4159), the Swedish Dental Society, the Swedish Society of Medicine, the County Council of Västerbotten, and AstraZeneca R&D Mölndal, Sweden. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1.

¹ To whom correspondence should be addressed. Tel.: 46-90-7856030; Fax: 46-90-770580; E-mail: Nicklas.Stromberg{at}odont.umu.se.

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