Nanostructures including hydrogels based on peptides containing non protein amino acids are being considered as platform for drug delivery because of their inherent biocompatibility and additional proteolytic stability. Here we describe instantaneous self-assembly of a conformationally restricted dipeptide, LeuΔPhe, containing an α,β-dehydrophenylalanine residue into a highly stable and mechanically strong hydrogel, under mild physiological aqueous conditions. The gel successfully entrapped several hydrophobic and hydrophilic drug molecules and released them in a controlled manner. LeuΔPhe was highly biocompatible and easily injectable. Administration of an antineoplastic drug entrapped in the gel in tumor bearing mice significantly controlled growth of tumors. These characteristics make LeuΔPhe an attractive candidate for further development as a delivery platform for various biomedical applications.
Inhibition of human islet amyloid polypeptide (hIAPP) fibrillisation by peptides incorporating a helicogenic amino acid, dehydrophenylalanine: implications for Type-2 diabetes.
Amyloid-β aggregation is a major etiological phenomenon in Alzheimer's disease. Herein, we report peptide-based inhibitors that diminish the amyloid load by obviating Aβ aggregation. Taking the hexapeptide fragment, Aβ32-37, as lead, more than 40 new peptides were synthesized. Upon evaluation of the newly synthesized hexapeptides as inhibitors of Aβ toxicity by the MTT-based cell viability assay, a number of peptides exhibited significant Aβ aggregation inhibitory activity at sub-micromolar concentration range. A hexapeptide (1) showed complete mitigation of Aβ toxicity in the cell culture assay at 2 μM. In the ThT fluorescence assay, upon incubation of Aβ with this peptide, we observed no increase in the ThT fluorescence relative to control. The secondary structure estimation by circular dichroism spectroscopy and morphological examination by transmission electron microscopy further confirmed the results.
Infections caused by Staphylococcal and Micrococcal species represent a major public health burden. Although treatments do exist, these tend to be associated with cytotoxic effects; furthermore, the emergence of antimicrobial resistance presents an immediate challenge. New classes of active compounds are required to address these threats to human health. Here we present a de novo peptidomimetic strategy that produces self‐assembling cationic antimicrobials. To identify a candidate compound with bactericidal activity, a small library of 8 peptidomimetics comprising ultrashort peptide sequences attached to a 3,5‐diaminobenzoic acid scaffold was generated and tested against Micrococcus luteus and Staphylococcus aureus. Self‐assembly appears to be the driving force for increased potency, likely by contributing to increased local surface charge density and peptide mass and producing a multivalent effect that enhances electrostatic interactions with negatively charged bacterial membranes, causing membrane disruption. The most active library member C7 forms patched micellar nanoparticles and has an activity higher than that of known natural antimicrobial peptides against M luteus. C7 also shows activity comparable to that of gramicidin S and the standard antibiotic vancomycin used in antibacterial therapy, but with a greater selectivity index. Importantly, C7 is also nontoxic and nonhemolytic, unlike the currently administered vancomycin, which can cause acute renal failure, and gramicidin S, which is highly hemolytic in nature. The short sequence length, ease of design, convenient synthesis strategy, and presence of a substitutable hydrophobic residue that enables self‐assembly into different nanostructures make this model compound highly attractive for generating cost‐effective, rapid‐acting peptide‐based antimicrobials.
Multicomponent self-assembly of peptides is a powerful strategy to fabricate novel functional materials with synergetic properties that can be used for several nanobiotechnological applications. In the present study, we used a coassembly strategy to generate an injectable ultrashort bioactive peptide hydrogel formed by mixing a dipeptide hydrogelator with a macrophage attracting short chemotactic peptide ligand. Coassembly does not impede hydrogelation as shown by cryo-transmission electron microscopy (cryo-TEM), scanning electron microscopy, and rheology. Biocompatibility was shown by cytotoxicity assays and confocal microscopy. The hydrogels release the entrapped skin antibiotic ciprofloxacin, among others, in a slow and continuous manner. Such bioinspired advanced functional materials can find applications as wound dressing materials to treat chronic wound conditions like diabetic foot ulcer.
Drug-resistant pathogenic fungi use several families of membrane-embedded transporters to efflux antifungal drugs from the cells. The efflux pump Cdr1 (Candida drug resistance 1) belongs to the ATP-binding cassette (ABC) superfamily of transporters. Cdr1 is one of the most predominant mechanisms of multidrug resistance in azole-resistant (AR) clinical isolates of Candida albicans. Blocking drug efflux represents an attractive approach to combat the multidrug resistance of this opportunistic human pathogen. In this study, we rationally designed and synthesized transmembrane peptide mimics (TMPMs) of Cdr1 protein (Cdr1p) that correspond to each of the 12 transmembrane helices (TMHs) of the two transmembrane domains of the protein to target the primary structure of the Cdr1p. Several FITC-tagged TMPMs specifically bound to Cdr1p and blocked the efflux of entrapped fluorescent dyes from the AR (Gu5) isolate. These TMPMs did not affect the efflux of entrapped fluorescent dye from cells expressing the Cdr1p homologue Cdr2p or from cells expressing a non-ABC transporter Mdr1p. Notably, the time correlation of single photon counting fluorescence measurements confirmed the specific interaction of FITC-tagged TMPMs with their respective TMH. By using mutant variants of Cdr1p, we show that these TMPM antagonists contain the structural information necessary to target their respective TMHs of Cdr1p and specific binding sites that mediate the interactions between the mimics and its respective helix. Additionally, TMPMs that were devoid of any demonstrable hemolytic, cytotoxic, and antifungal activities chemosensitize AR clinical isolates and demonstrate synergy with drugs that further improved the therapeutic potential of fluconazole in vivo.
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