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Chemical Structure| 154445-77-9 Chemical Structure| 154445-77-9
Chemical Structure| 154445-77-9

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Singh, Harminder ; Biswas, Diptomit ; Medina, Scott ;

Abstract: Implant contamination by bacterial biofilms remains a significant healthcare burden, often necessitating revision surgeries due to biofilm-enabled antibiotic resistance. Physical debridement, in combination with chemical antiseptics, is a simple and effective therapeutic strategy, but requires highly invasive surgical procedures and risks secondary infection events. Herein, we report a non-invasive, nanoparticle-enabled ultrasonic debridement strategy that exerts synergistic physical and chemical antiseptic effects to rapidly and efficiently clear implant-associated biofilms in situ. This approach is realized through the development of hydrogen sulfide- releasing peptide nanoemulsions that preferentially target bacterial biofilms and can be vaporized via diagnostic ultrasound to spatiotemporally clear methicillin-resistant Staphylococcus aureus (MRSA) infections. Biophysical studies elucidate the mechanistic basis for the platform’s antibiofilm activity, and in vitro and ex vivo experiments confirm efficacy in the context of MRSA-infected titanium implants. By exploiting the portable, low cost and safe nature of low intensity diagnostic ultrasound, this non-invasive approach avoids the collateral tissue damage associated with current surgical and high intensity acoustic ablative modalities.

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Calabretta, Lindsey O. ; Yang, Jinyi ; Raines, Ronald T. ;

Abstract: The field of cell-penetrating peptides is dominated by the use of oligomers of arginine residues. Octanol-water partitioning in the presence of an anionic lipid is a validated proxy for cell-penetrative efficacy. Here, we add one, two, or three N-Me groups to Ac-Arg-NH2 and examine the effects on octanol-water partitioning. In the absence of an anionic lipid, none of these arginine derivatives can be detected in the octanol layer. In the presence of sodium dodecanoate, however, increasing N-methylation correlates with increasing partitioning into octanol, which is predictive of higher cell-penetrative ability. We then evaluated fully Nα-methylated oligoarginine peptides and observed an increase in their cellular penetration compared with canonical oligoarginine peptides in some contexts. These findings indicate that a simple modification, Nα-methylation, can enhance the performance of cell-penetrating peptides.

Keywords: guanidino group ; octanol-water partitioning ; peptoid ; topological polar surface area

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Orgren Calabretta, Lindsey ;

Abstract: The delivery of biological molecules into cells has been an issue of importance in both chemical biology and drug discovery. One method used to transport biologics into cells is the cellpenetrating peptide (CPP). This arginine-rich peptide forms strong interactions with the cell surface through bidentate guanidinium–oxoanion hydrogen bonds. Depending on conditions, this interaction guides the uptake of the CPP and its cargo through direct translocation or endocytosis. In Chapter 1, I summarize literature that is relevant to this thesis. In Chapter 2, I describe the synthesis and characterization of a small molecule, 1- guanidino-8-amino-2,7-diazacarbazole dichloride (GADAC), that displays a high binding affinity to a carboxylate, phosphate, and sulfate in water. GADAC is also fluorescent and displays an increase in quantum yield mediated by pH. The uptake and fluorescence of GADAC is observed in human melanoma cells via epifluorescent microscopy. Thus, the GADAC scaffold shows promise as a potential cell-uptake promoter and fluorescent reporter of biologics. In Chapters 3 and 4, I explore alternative amino acids for use in CPPs. I studied the ability of canavanine, a -oxa-analog of arginine, to partition into octanol in the presence of anionic lipids as a proxy for its cell-penetration ability. I observed that canavanine is worse at partitioning than arginine, indicating it may not be an effective CPP alternative. In contrast, I synthesized and performed anion-mediated partitioning on Nα-methylated arginine derivatives and observed increased octanol uptake compared to unmethylated arginine. This increased uptake is correlates with a decrease in topological polar surface area (TPSA) and indicates that an Nα-methylated CPP could be a cell-uptake promoter with increased efficacy. Lastly, in Chapter 4, I describe the synthesis of biaryl-bisguanidines. These guanidines are inspired by axially constrained organometallic catalyst ligands and have applications in oxoanion binding as dications and organometallic catalysts as dianions. I detail initial forays into determining the binding affinities of the guanidines to oxoanions through NMR titration experiments, which were hampered by changing ionic strength of the solutions. Appendices describe the synthesis of photocaged phosphinothioesters for the traceless Staudinger ligation and attempts to install a diazo moiety site-selectively at the N-terminus of a peptide or protein.

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Product Details of Fmoc-Arg(Pbf)-OH

CAS No. :154445-77-9
Formula : C34H40N4O7S
M.W : 648.77
SMILES Code : O=C(O)[C@@H](NC(OCC1C2=C(C3=C1C=CC=C3)C=CC=C2)=O)CCCNC(NS(=O)(C4=C(C)C(C)=C(OC(C)(C)C5)C5=C4C)=O)=N
MDL No. :MFCD00235804
InChI Key :HNICLNKVURBTKV-NDEPHWFRSA-N
Pubchem ID :11354259

Safety of Fmoc-Arg(Pbf)-OH

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338
 

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