Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy

Abstract

Antimicrobial peptides (AMPs) have recently gained attention as a viable solution for combatting antibiotic resistance due to their numerous advantages, including their broad-spectrum activity, low propensity for inducing resistance, and low cytotoxicity. Unfortunately, their clinical application is limited due to their short half-life and susceptibility to proteolytic cleavage by serum proteases. Indeed, several chemical strategies, such as peptide cyclization, N-methylation, PEGylation, glycosylation, and lipidation, are widely used for overcoming these issues. This review describes how lipidation and glycosylation are commonly used to increase AMPs’ efficacy and engineer novel AMP-based delivery systems. The glycosylation of AMPs, which involves the conjugation of sugar moieties such as glucose and N-acetyl galactosamine, modulates their pharmacokinetic and pharmacodynamic properties, improves their antimicrobial activity, and reduces their interaction with mammalian cells, thereby increasing selectivity toward bacterial membranes. In the same way, lipidation of AMPs, which involves the covalent addition of fatty acids, has a significant impact on their therapeutic index by influencing their physicochemical properties and interaction with bacterial and mammalian membranes. This review highlights the possibility of using glycosylation and lipidation strategies to increase the efficacy and activity of conventional AMPs.

Impacts of PEGylation and Glycosylation on the Biological Properties of Host Defense Peptide IDR1018

“…When incubated with PBMCs in tissue culture, neither peptide conjugate, PEG6-IDR1018, and Glc-IDR1018 showed any obvious sign of aggregation, in strong contrast to IDR1018, which showed amorphous aggregates ( Figure 1 d). These results, indeed, were consistent with earlier reports, that demonstrated the utility of pegylation and glycosylation in increasing solubility and diminishing aggregation for other antimicrobial peptides [ 31 , 41 ].…”

“…Nevertheless, despite these advantages, pegylation is often associated with a partial or complete reduction in the antimicrobial activity of HDPs [ 30 ]. Glycosylation is a process by which a sugar moiety is chemically attached to biopharmaceutical molecules such as peptides, proteins, antibodies, etc., in order to change their physicochemical properties or produce better bioactive compounds [ 31 ]. As with pegylation, glycosylation can have a significant influence on the properties of HDPs, for example, modifying toxicities, resistance to proteolytic degradation, pharmacokinetics and dynamic properties [ 27 , 31 , 32 ].…”

“…Glycosylation is a process by which a sugar moiety is chemically attached to biopharmaceutical molecules such as peptides, proteins, antibodies, etc., in order to change their physicochemical properties or produce better bioactive compounds [ 31 ]. As with pegylation, glycosylation can have a significant influence on the properties of HDPs, for example, modifying toxicities, resistance to proteolytic degradation, pharmacokinetics and dynamic properties [ 27 , 31 , 32 ]. However, as with pegylation, glycosylation does not always improve the antibacterial activity of HDPs since the attaching surges change the chemical structure, hydrophobicity and overall charge of the peptides, which can impact the insertion and interaction of peptides with bacterial membranes [ 31 ].…”

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies

“…Sugar groups can be linked to proteins in various ways. For example, by covalently linking the glycoside moiety to the Ser or Thr side chain (O-glycosylation), or to the amide bond of the Asn side chain (N-glycosylation) (Figure 5B); 199 glucose and xylose are the most widely used. There are many opioid peptide analogues, such as delta kephalin, cyclic methionine enkephalin analogues, and linear leucine enkephalin analogues.…”

Tuning of hydrophobic–hydrophilic balance for the development of a salt-tolerant and protease-resistant lipopeptide AMP

“…21 Thus, the design principles of synthetic AMPs aim to (a) increase the antimicrobial potency, (b) increase the in vivo efficiency through salt tolerance of the activity and the resistance against proteolytic degradation and (c) decrease the cytotoxicity. 22–25 Different strategies, such as lipidation, 26 cyclization, 27 glycosylation, 28 incorporation of unnatural amino acid residues, 29 terminal modification and multimerization, 30 have been adopted for developing futuristic AMP therapeutics. 31 Lipopeptides are a class of amphiphilic AMPs that show high antimicrobial potency.…”