PEGylation of the antimicrobial peptide LyeTx I-b maintains structure-related biological properties and improves selectivity

Brito, Júlio César Moreira; Carvalho, Lucas Raposo; Souza, Amanda Neves de; Carneiro, Guilherme; Magalhães, Paula Prazeres; Farias, Luiz M.; Guimarães, Natália Rocha; Verly, Rodrigo M.; Resende, Jarbas M.; Lima, Maria Elena de

doi:10.3389/fmolb.2022.1001508

Cited by 10 publications

(5 citation statements)

References 60 publications

(86 reference statements)

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“…Compared to the parent IDR1018 peptide, which appeared to be hemolytic against RBCs as well as toxic to PBMCs at high doses (up to 20% at 128 µg mL −1 ), neither of the conjugated derivatives exhibited any hemolysis or cytotoxicity at the highest concentration tested (Figure 2a,b). Consistent with other previous studies for other peptides [30,31,42,43], pegylation and glycosylation worked well in reducing HDP toxicity. The capacity of conjugated peptide derivatives to modulate the innate immune system was tested by assessing the induction and suppression of chemokines and cytokines from human PBMCs.…”

Section: Hemolysis Cytotoxicity and Immunomodulatory Activitysupporting

confidence: 91%

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

2023

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The multifunctional properties of host defense peptides (HDPs) make them promising drug candidates to tackle bacterial infections and tissue inflammation. However, these peptides tend to aggregate and can harm host cells at high doses, potentially limiting their clinical use and applications. In this study, we explored the influences of both pegylation and glycosylation on the biocompatibility and biological properties of HDPs, particularly the innate defense regulator IDR1018. Two peptide conjugates were designed by attaching either polyethylene glycol (PEG6) or a glucose moiety to the peptide towards the N-terminus. Significantly, both derivatives reduced the aggregation, hemolysis, and cytotoxicity of the parent peptide by orders of magnitude. In addition, while the pegylated conjugate, PEG6-IDR1018, retained an excellent immunomodulatory profile, similar to that observed for IDR1018 itself, the glycosylated conjugate, Glc-IDR1018, significantly outperformed the parent peptide in inducing anti-inflammatory mediators, MCP1 and IL-1RA and in suppressing the level of lipopolysaccharide-induced proinflammatory cytokine IL-1β. Conversely, the conjugates led to a partial reduction in antimicrobial and antibiofilm activity. These findings underline the impacts of both pegylation and glycosylation on the biological properties of the HDP IDR1018 and indicate the potential of glycosylation to enhance the design of highly effective immunomodulatory peptides.

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Section: Hemolysis Cytotoxicity and Immunomodulatory Activitysupporting

confidence: 91%

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

2023

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“…conjugation targeted site-specific amino acids, including lysine (Lys), Cys, arginine (Arg), and Tyr, which can increase the molecular size of the peptide. PEGylation has been reported to increase oxytocin stability at high temperatures [ 124 ], extending the biological activities of Human Pancreatic Polypeptide (hPP) [ 151 ] and minimizing side effects of antimicrobial peptides LyeTx I-b [ 152 ]. Although it is rare, it has been found that patients can develop allergic reactions to P.E.G.…”

Section: Strategies To Optimize Peptide Stability In Aqueous Formulat...mentioning

confidence: 99%

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

et al. 2023

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Over the past few decades, there has been a tremendous increase in the utilization of therapeutic peptides. Therapeutic peptides are usually administered via the parenteral route, requiring an aqueous formulation. Unfortunately, peptides are often unstable in aqueous solutions, affecting stability and bioactivity. Although a stable and dry formulation for reconstitution might be designed, from a pharmaco-economic and practical convenience point of view, a peptide formulation in an aqueous liquid form is preferred. Designing formulation strategies that optimize peptide stability may improve bioavailability and increase therapeutic efficacy. This literature review provides an overview of various degradation pathways and formulation strategies to stabilize therapeutic peptides in aqueous solutions. First, we introduce the major peptide stability issues in liquid formulations and the degradation mechanisms. Then, we present a variety of known strategies to inhibit or slow down peptide degradation. Overall, the most practical approaches to peptide stabilization are pH optimization and selecting the appropriate type of buffer. Other practical strategies to reduce peptide degradation rates in solution are the application of co-solvency, air exclusion, viscosity enhancement, PEGylation, and using polyol excipients.

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“…Other strategies include (i) PEGylation [ 39 , 40 ], which allows for greater solubility and stability in aqueous solutions while reducing renal clearance [ 41 ]; (ii) glycosylation involving carbohydrate conjugation, which broadens peptide diversity by extending their properties and functions [ 42 ]; and (iii) lipidation involving the covalent attachment of fatty acids, which affects peptide activity through several mechanisms [ 43 , 44 ].…”

Section: Structural Modification Of Ampsmentioning

confidence: 99%

Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy

et al. 2023

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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.

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PEGylation of the antimicrobial peptide LyeTx I-b maintains structure-related biological properties and improves selectivity

Cited by 10 publications

References 60 publications

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

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

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy

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