Click scaffolds for inhibition of P. gingivalis biofilm formation

Objectives: Periodontitis and its systemic sequelae remain a major public health problem and developing a cost-efficient therapy will benefit healthcare worldwide. Adherence of Porphyromonas gingivalis to Streptococcus gordonii facilitates colonization of the oral cavity by P. gingivalis and contributes to development of periodontal disease. It was previously shown that a synthetic peptide derived from the streptococcal protein SspB potently inhibits this interaction and prevents formation of P. gingivalis biofilms. However, peptides are not ideal therapeutic agents. Consequently, our approach was to rationally-design small-molecule peptidomimetics that inhibit P. gingivalis adherence to S. gordonii that may represent viable therapeutic compounds.

Methods: In terms of inhibitor design, a small molecule “click chemistry” strategy was employed whereby the azide-bearing partner constitutes a trisubstituted oxazole framework and the terminal acetylene partner constitutes a 1, 3-diaminotriazine framework.

Results: The design, synthesis and chemistry of the coupling partners in both the acetylenic and azido series have been accomplished. Four azido compounds have been synthesized and one acetylenic compound.  The backbone structure of the acetylenic compound was tested for inhibition of P. gingivalis adherence to streptococci and was shown to block adherence by 25% and 67% at concentrations of 25µM and 50µM, respectively. 

Conclusions: Bio-active small molecule peptidomimetics were synthesized that may represent therapeutic agents that could reduce P. gingivalis colonization of the oral cavity.