Glucose–Lipopeptide Conjugates Reveal the Role of Glucose Modification Position in Complexation and the Potential of Malignant Melanoma Therapy

Abstract

Glycosylation and fatty acid modification are promising strategies to improve peptide performance. We previously studied glycosylation and fatty acid modification of the anticancer peptide R-lycosin-I. In this study, we further investigated the comodification of fatty acids and monosaccharides in R-lycosin-I. A glucose derivative was covalently coupled to the ε-amino group of the Lys residues of the lipopeptide R-C 12 , which was derived from R-lycosin-I modified with dodecanoic acid, and obtained seven glycolipid peptides. They exhibited different cytotoxicity profiles, which may be related to the changes in physicochemical properties and binding ability to glucose transporter 1 (GLUT1). Among them, R-C 12 -4 exhibited the highest cytotoxicity and improved selectivity. A further study demonstrated that R-C 12 -4 showed significant cytotoxicity and antimetastasis activity in murine melanoma cells, melanoma spheroids, and animal models. Our results indicated that the glucose derivative modification position plays important roles in glucose−lipopeptide conjugates, and R-C 12 -4 might be a promising lead for developing anticancer drugs.

Dual-sensitive antibacterial peptide nanoparticles prevent dental caries

“…(1) Considering the importance of the positive charge in pH-responses of peptides, histidine was used to selectively replace the lysine residues in lycosin-I as the pH-responsive moiety to control the assembly and disassembly of a peptide due to its relatively low pKa value compared to lysine. (2) The electrostatic interaction between cationic AMPs and microbial membranes with negative charges of lipids, such as phosphatidylglycerol (PG), is the initial step in exerting antibacterial activity 27 - 29 . Hence, the negatively charged glutamic acid residues within lycosin-I were exchanged for neutral glutamine residues.…”

One New Acid-Activated Hybrid Anticancer Peptide by Coupling with a Desirable pH-Sensitive Anionic Partner Peptide

“…Anticancer peptides (ACPs) have been introduced as alternative candidates to treat cancer with a certain degree of cancer cell selectivity, low tendency to drug resistance, good biocompatibility, and ease of synthesizing and modifying. − Generally, they are relatively small peptides with variable cationic and amphipathic characteristics. They exhibit broad-spectrum antitumor activity through multiple action mechanisms. − One prominent merit of ACPs is that these peptides could selectively disrupt the tumor cell membrane in a receptor-independent manner, which is different from that of conventional antineoplastic agents. , Despite this, the drawbacks of anticancer peptides, such as the toxicity at high concentrations and fast degradation in vivo, are still the main concerns for drug development. , To circumvent these limitations, many different strategies have been used to improve the therapeutic efficiency of ACPs, including amino acid substitution, − fatty acid modification, , glycosylation, , backbone conjugation or cyclization, , and utilization of functionalized carriers. , Histidine modification is a simple and effective approach to develop smart pH-responsive ACPs with better selectivity for cancer therapy based on the tumor acidic environment, as histidine could protonate into a positive charge under the acidic tumor microenvironment from predominantly no charge in tissues with normal physiological conditions, thereby endowing peptides with a pH-activated charge conversion feature. , Hence, this type of histidine-based ACPs is inactivated under physiological conditions, while their antitumor activity can be activated in an acidified tumor microenvironment. Notably, the combination of unique histidine with negatively charged glutamate (Glu) is also a promising approach to obtaining acid-responsive recombinant peptides. , The cationic charge of these peptides can be first shielded by anionic glutamate under normal physiological conditions to alleviate their indiscriminative effect.…”

“… 19 , 20 Despite this, the drawbacks of anticancer peptides, such as the toxicity at high concentrations and fast degradation in vivo, are still the main concerns for drug development. 14 , 15 To circumvent these limitations, many different strategies have been used to improve the therapeutic efficiency of ACPs, including amino acid substitution, 21 − 23 fatty acid modification, 24 , 25 glycosylation, 25 , 26 backbone conjugation or cyclization, 27 , 28 and utilization of functionalized carriers. 29 , 30 Histidine modification is a simple and effective approach to develop smart pH-responsive ACPs with better selectivity for cancer therapy based on the tumor acidic environment, 31 as histidine could protonate into a positive charge under the acidic tumor microenvironment from predominantly no charge in tissues with normal physiological conditions, thereby endowing peptides with a pH-activated charge conversion feature.…”

Enhanced Uptake of Anticancer C6-Pep Dimer in a Model Membrane Caused by Differential pKa in Acidic Microenvironment

“…12 Direct binding of glucose transporter I (GLUT I) with lipopeptide R-C 12 linked glucose derivatives has resulted in antimetastasis activity against murine melanoma cells. 10 Since immune cell activity is suppressed in TME, lipopeptide agonists like Pam 3 CSK 4 , MALP2, and FSL-1 linked with MUC1 glycopeptide have been used to directly activate antigen-presenting cells (APC) and act as self-adjuvanting cancer vaccines. 9,15 Leucine zipper (ZIP) motifs with heptad repeat of leucine residues and α-helix conformation have been found in gene regulatory proteins and transcription factors and are a part of protein−protein interactions.…”

“…Lipopeptides, having a surfactant-like property due to the presence of amphiphilic proteins at one end and hydrophobic lipid tails at the other end, are excellent candidates for drug delivery vehicles of chemo drugs, part of cancer vaccines, and anticancer peptides for direct action against tumors by exploiting the acidic nature of TME around the tumor cells. − Wang et al have synthesized a molecule consisting of folic acid for recognizing the target site, a dipeptide linker, and a peptide prodrug, which self-assembles into a nanoparticle at pH = 7 and into nanofibers at pH = 5 . This pH-based change in self-assembled structure allows for the self-delivery of the prodrug into TME.…”