‘Second-generation’ 1,2,3-triazole-based inhibitors of <i>Porphyromonas gingivalis</i> adherence to oral streptococci and biofilm formation

Patil, Pravin; Tan, Jinlian; Demuth, Donald R.; Luzzio, Frederick A.

doi:10.1039/c8md00405f

Cited by 12 publications

(10 citation statements)

References 39 publications

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“…Therefore, disruption of heterotypic community formation by targeting the Mfa1/antigen I/II interaction may represent a potential therapeutic approach to control P. gingivalis colonization and virulence (Daep et al, ; Sztukowska, Roky, & Demuth, ; Tan et al, ). The region of antigen I/II involved in the interaction with Mfa1 has been extensively characterized (Daep, James, Lamont, & Demuth, ; Daep et al, , ; Daep, Novak, Lamont, & Demuth, ) and these studies led to the development of both peptide and small molecule peptidomimetics that potently inhibit P. gingivalis /streptococcal adherence in vitro and significantly reduced P. gingivalis virulence in vivo (Daep et al, ; Patil et al, ; Patil, Tan, Demuth, & Luzzio, ; Tan et al, ). However, the interacting interface of Mfa1 that drives this protein–protein interaction has not been well characterized.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that these residues may not interact directly with Ag I/II (or the BAR peptide), or alternatively, that they may also require the contribution of downstream residues. Since Mfa1 has been recently crystallized (Hall et al, ), it may be possible to co‐crystallize the protein with the BAR peptide or with recently developed peptidomimetics of BAR (Patil et al, ) to generate a more complete picture of the Mfa1‐Ag I/II interacting interface. Ultimately, a thorough understanding of the mechanism of the Mfa1/Ag I/II interaction will facilitate structure‐based drug design and the development of potential therapeutics that may limit P. gingivalis colonization of the oral cavity.…”

Section: Discussionmentioning

confidence: 99%

“…gingivalis/streptococcal adherence in vitro and significantly reduced P. gingivalis virulence in vivo (Daep et al, 2011;Patil et al, 2016;Patil, Tan, Demuth, & Luzzio, 2019;Tan et al, 2018). However, the interacting interface of Mfa1 that drives this protein-protein interaction has not been well characterized.…”

Section: Discussionmentioning

confidence: 99%

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Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci

Roky

Trent

Demuth

2020

Molecular Oral Microbiology

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Porphyromonas gingivalis is associated with chronic periodontitis and may initially colonize the oral cavity by adhering to streptococci. Adhesion to streptococci is driven by interaction of the minor fimbrial antigen (Mfa1) with streptococcal antigen I/II. We identified the region of antigen I/II required for this interaction and developed small molecule mimetics that inhibited P. gingivalis adherence. However, the functional motifs of Mfa1 involved in the interaction with antigen I/II remain uncharacterized. A series of N‐ and C‐terminal peptide fragments of Mfa1 were expressed and tested for inhibition of P. gingivalis adherence to S. gordonii. This approach identified residues 225–400 of Mfa1 as essential for P. gingivalis adherence. Using the three‐dimensional structure of Mfa1, a putative binding cleft was identified using SiteMap and five small molecule mimetics could dock in this site. Site‐specific mutation of residues in the predicted cleft, including R240A, W275A, D321A and A357P inhibited the interaction of Mfa1 with streptococci, whereas mutation of residues not in the predicted cleft (V238A, I252F and ΔK253) had no effect. Complementation of an Mfa1‐deficient P. gingivalis strain with wild‐type mfa1 restored adherence to streptococci, whereas complementation with full‐length mfa1 containing the R240A or A357P mutations did not restore adherence. The mutations did not affect polymerization of Mfa1, suggesting that the complemented strains produced intact minor fimbriae. These results identified specific residues and structural motifs required for the Mfa1‐antigen I/II interaction and will facilitate the design of small molecule therapeutics to prevent P. gingivalis colonization of the oral cavity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci

Roky

Trent

Demuth

2020

Molecular Oral Microbiology

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“…All four of the active first generation mimetics were subsequently shown to inhibit P. gingivalis virulence in vivo and exhibited minimal levels of toxicity towards various human and mouse cell lines (Tan et al, ). Recently, Patil, Tan, Demuth, and Luzzio () reported the synthesis of second generation 1,2,3‐triazole‐based inhibitors which utilized a 1,3,5‐trisubstituted‐2,4,6‐triazine scaffold to mimic the VXXLL motif. This scaffold was based on a structure that was used to mimic the core LXXLL motif in the eukaryotic NR box.…”

Section: Small Molecule Inhibitors Targeting Oral Bacteriamentioning

confidence: 99%

Peptide and non‐peptide mimetics as potential therapeutics targeting oral bacteria and oral biofilms

Sztukowska

Roky

Demuth

2019

Molecular Oral Microbiology

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The development of the oral biofilm requires a complex series of interactions between host tissues and the colonizing bacteria as well as numerous interspecies interactions between the organisms themselves. Disruption of normal host–microbe homoeostasis in the oral cavity can lead to a dysbiotic microbial community that contributes to caries or periodontal disease. A variety of approaches have been pursued to develop novel potential therapeutics that are active against the oral biofilm and/or target specific oral bacteria. The structure and function of naturally occurring antimicrobial peptides from oral tissues and secretions as well as external sources such as frog skin secretions have been exploited to develop numerous peptide mimetics and small molecule peptidomimetics that show improved antimicrobial activity, increased stability and other desirable characteristics relative to the parent peptides. In addition, a rational and minimalist approach has been developed to design small artificial peptides with amphipathic α‐helical properties that exhibit potent antibacterial activity. Furthermore, with an increased understanding of the molecular mechanisms of beneficial and/or antagonistic interspecies interactions that contribute to the formation of the oral biofilm, new potential targets for therapeutic intervention have been identified and both peptide‐based and small molecule mimetics have been developed that target these key components. Many of these mimetics have shown promising results in in vitro and pre‐clinical testing and the initial clinical evaluation of several novel compounds has demonstrated their utility in humans.

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“…11,12 Along with high regioselectivity, carbon atoms are coordinated on the electron cloud density change without end group of copper ion catalytic acetylene and azide. 13,14 In most cases, the 3-dipole ring addition reaction is not regionally selective and the reaction is slow. 15,16 Biomolecules have hardly reacted with azide and alkyne group, due to the weak polarity of the latter two ones.…”

Section: Introductionmentioning

confidence: 99%

A Brief Minireview of poly-triazole: Alkyne and Azide Substrate Selective, Metal-catalyst Design

Huo¹,

Wang²,

Liang³

et al. 2019

Preprint

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‘Second-generation’ 1,2,3-triazole-based inhibitors of Porphyromonas gingivalis adherence to oral streptococci and biofilm formation

Abstract: This study details the design, synthesis and bioassay of ‘click’ peptidomimetic compounds which inhibit the adherence of P. gingivalis to S. gordonii, a primary step toward pathogenic colonization of the subgingival pocket.

Cited by 12 publications

References 39 publications

Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci

Identification of functional domains of the minor fimbrial antigen involved in the interaction of Porphyromonas gingivalis with oral streptococci

Peptide and non‐peptide mimetics as potential therapeutics targeting oral bacteria and oral biofilms

A Brief Minireview of poly-triazole: Alkyne and Azide Substrate Selective, Metal-catalyst Design

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