We report a series of lipidated α-AApeptides that mimic the structure and function of natural antimicrobial lipopeptides. Several short lipidated α-AApeptides show broadspectrum activity against a range of clinically related Grampositive and Gram-negative bacteria as well as fungus. Their antimicrobial activity and selectivity are comparable or even superior to the clinical candidate pexiganan as well as previously reported linear α-AApeptides. The further development of lipidated α-AApeptides will lead to a new class of antibiotics to combat drug resistance. KEYWORDS: antimicrobial peptides, peptidomimetics, drug resistance, lipidation, α-AApeptides A ntimicrobial peptides (AMPs) are found in most living organisms as an integral component of their innate defense against invading pathogens.1,2 Unlike conventional antibiotics that target specific substrates involved in bacterial metabolism, AMPs are believed to kill bacteria via a nonspecific interaction with their membranes, which has less chance of inducing the development of resistance by bacteria.1,2 Short cationic amphiphilic AMPs tend to interact with the negatively charged phospholipids on the bacterial membrane, which accounts for their selectivity for bacteria against eukaryotic cells whose membranes are more zwitterionic.3,4 Because of their selectivity for bacteria, low propensity for development of drug resistance, and broad-spectrum antimicrobial potency, AMPs are considered an emerging class of antimicrobial agents. 1−3 Nevertheless, the therapeutic application of AMPs is impeded by their intrinsic instability in the context of proteolytic degradation.1,2 Bactericidal peptidomimetics comprised of unnatural amino acids were thereby developed to circumvent the drawbacks of AMPs, which are protease-resistant and of improved bioavailability. 5 In recent years, several peptidomimetic analogues of AMPs, such as β-peptides, 6−9 arylamides, 10,11 and peptoids, 3,12,13 have received significant research interest.Lipidated peptides such as polymyxin B 14 and daptomycin 15 are lipo-antibiotics, which possess fatty acid tails that are integral to their bactericidal activities. It has been shown that attachment of saturated linear fatty acids to peptide termini greatly enhanced AMPs' antimicrobial activities toward both Gram-positive and Gram-negative strains. 16−19 More recently, short peptoid mimetics alkylated with lipids of 10 or 13 carbons were demonstrated to bear improved selectivity, without losing any antimicrobial activities. 13 It was suspected that lipid alkylation improves the hydrophobicity of charged peptides 18 and facilitates the interaction with cytoplasmic membranes.18 It is thereby envisioned that the development of lipidated peptidomimetics may overcome some of the drawbacks associated with current lipopeptide antibiotics. Herein, we report the development of lipidated α-AApeptides as potential antimicrobial agents. We have recently developed a novel class of peptidomimetics based on the α-chiral PNA (peptide nucleic acid) back...

The solid-phase synthesis of γ-AApeptides using a novel submonomeric approach that utilizes an allyl protection is reported. The strategy successfully circumvents the necessity of preparing γ-AApeptide building blocks in order to prepare γ-AApeptide sequences. This method will maximize the potential of developing chemically diverse γ-AApeptide libraries and thereby facilitate the biological applications of γ-AApeptides in the future.

Although peptide amphiphiles have been explored as nanomaterials for different applications, nanostructures formed by hierarchical molecular assembly of sequencespecific peptidomimetics are much less developed. Such protein-like nanomaterials could enhance the current application of peptide-based amphiphiles by enriching the diversity of nanostructures, increasing in vivo stability for biomedical applications, and facilitating the understanding of biomacromolecular self-assembly. Herein we present a biomimetic γ-AApeptide amphiphile which forms nanorods. Our results demonstrate the capability of γ-AApeptide amphiphiles as a potential scaffold for the preparation of biomimetic and bioinspired nanostructures. The programmability and biocompatibility of γ-AApeptides could lead to novel nanomaterials for a wide variety of applications. ■ INTRODUCTIONMolecular self-assembly is ubiquitous and vitally important in nature. Through noncovalent interactions, monomeric units self-assemble together to construct complex systems with unique biological functions. 1 Examples of such hierarchical molecular assembly found in nature include self-assembly of lipids, proteins, and nucleic acids. 2 Research on molecular selfassembly is critical in nanotechnology because it sheds light on the understanding of molecular assembly mechanisms, the design of building blocks and monomeric units, and the construction of nanostructures and nanomaterials with desired functions. 3 There has been extensive interest in the development of peptide-based nanomaterials in the past decade, and their applications as nanomaterials, nanotechnology, and nanomedicines have been widely explored. 3 In these cases, polypeptides are used as monomer units to self-assemble into ordered nanostructures so as to develop novel functional nanobiomaterials that can mimic protein structures and functions. 4,5 This is because there are 20 natural amino acids that can be used as building blocks to construct an enormous number of peptides and proteins with a wide variety of lengths, hydrophobicity/hydrophilicity, and shapes, which leads to the formation of different nanostructures through self-assembly. 3 Among these peptide-based nanomaterials, peptide amphiphiles are mostly used to generate self-assembled nanostructures in aqueous environment. 6 Peptide amphiphiles consist of a hydrophilic peptide head with desired structures and functions and a hydrophobic tail. In aqueous solution, the hydrophobic tail, normally an alkyl chain, lipid, or hydrophobic peptide, induces the aggregation of peptide amphiphiles. Meanwhile, the hydrophilic heads, consisting of polar or charged amino acid residues, assemble into nanostructures through hydrophilic interactions with water and other molecules. So far, the nanostructures generated by peptide amphiphiles include nanotubes, nanorods, nanovesicles, micelles, nanobelts, and nanofibers. 7−13 However, despite tremendous effort in the development of peptide-based nanomaterials, non-natural oligomeric peptidomimetic-based nanomaterials hav...

Current cancer treatment methods are still inadequate due to the complexity of the cancer progression mechanism, which involves multiple genes, proteins, and signaling pathways. The discovery and validation of novel anticancer compounds remains challenging. Garlic has many medicinal properties that can combat various diseases. Organosulfur present in garlic has been shown to induce apoptosis in cancer cells; however, the underlying mechanism of action of non-organosulfur compounds from garlic in controlling cancer cells remains unclear. The present study aimed to analyze the efficacy of organosulfur and non-organosulfur compounds, including the flavonoid, terpenoid, and saponin groups, as inhibitors of C-C chemokine receptor type 5 (CCR5) and C-X-C chemokine receptor type 4 (CXCR4), which play significant roles in the progression of cancer. To determine the interactions between the active compounds of garlic and these receptors (CCR5 and CXCR4), molecular docking was performed using the PyRx v.0.8 software. Amino acid residues were analyzed and visualized using Biovia Discovery Studio and PyMol, respectively. Non-organosulfur compounds exhibited better results than the organosulfur compounds in binding affinity analysis. Tigogenin (from the saponin group) is considered to be a CCR5 inhibitor, while lupeol (from the terpenoid group) is considered to be a CXCR4 inhibitor. In conclusion, our results suggest that garlic compounds could be promising inhibitors of CCR5 and CXCR4, which are highly expressed in cancer. However, further research is needed to validate the in vitro and in vivo activities of garlic compounds for the inhibition of cancer progression. Keywords: Anticancer agents, CCR5, CXCR4, Garlic, Organosulfur compounds, Non-Organosulfur compounds]