Strategies for Improving Peptide Stability and Delivery

Musaimi, Othman Al; Lombardi, Lucia; Alberício, Fernando

doi:10.3390/ph15101283

Cited by 79 publications

(49 citation statements)

References 86 publications

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“…This technique involves the formation of ion pairs between a hydrophobic counterion and a positively charged amino acid residue in the peptide, typically His, Lys, or Arg. This interaction effectively shields the charged groups from the surrounding solvent, reducing their exposure to water and potential hydrolysis [ 196 , 197 , 198 ].…”

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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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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“…The basic processes for continuing to increase the stability of therapeutic peptides include N- and/or C-terminal reconfiguration (N-acylation or N-formylation at the N-terminal end, C-termination amidation) and even partial replacement, reconfiguration of the backbone, conversion of peptides with the d -amino acid or unnatural amino acid, crosslinking, nanoparticle formulations of the peptides, and/or by increasing the molecular mass. Conjugating the peptide with polymer also increases the stability of the peptide; for example, polyethylene glycol (PEG) is the most promising polymer [ 24 – 26 ]. On the other hand, AVP1235 and AVP1788 are both stable in nature, but AVP 1235 has a half-life of 30 h compared to the 4.4 h of AVP 1788.…”

Section: Resultsmentioning

confidence: 99%

Identification of multi-targeting natural antiviral peptides to impede SARS-CoV-2 infection

et al. 2022

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SARS-CoV-2 and its variants cause serious health concerns throughout the world. The alarming increase in the daily number of cases has become a nightmare in many low-income countries; although some vaccines are available, their high cost and low vaccine production make them unreachable to ordinary people in developing countries. Other treatment strategies are required for novel therapeutic options. The peptide-based drug is one of the alternatives with low toxicity, more specificity, and ease of synthesis. Herein, we have applied structure-based virtual screening to identify potential peptides targeting the critical proteins of SARS-CoV-2. Non-toxic natural antiviral peptides were selected from the enormous number of peptides. Comparative modeling was applied to prepare a 3D structure of selected peptides. 3D models of the peptides were docked using the ClusPro docking server to determine their binding affinity and peptide-protein interaction. The high-scoring peptides were docked with other crucial proteins to analyze multiple targeting peptides. The two best peptides were subjected to MD simulations to validate the structure stability and evaluated RMSD, RMSF, Rg , SASA, and H-bonding from the trajectory analysis of 100 ns. The proposed lead peptides can be used as a broad-spectrum drug and potentially develop as a therapeutic to combat SARS-CoV-2, positively impacting the current pandemic. Supplementary Information The online version contains supplementary material available at 10.1007/s11224-022-02113-9.

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“…PTDs is a promising technology that facilitates the transport of proteins through cell membranes, thus allowing us to consider a protein-based therapeutic modality to treat human disorders that traditionally have been avoided due to membrane permeability issues. Since their discovery [ 173 , 174 , 178 , 179 ], the number of known PTDs is steadily growing, and their transduction efficiency continues to improve [ 189 , 190 ]. In vitro and in vivo models of neurological disorders, rare genetic disorders, heart diseases, and cancer are some models in which PTDs have been evaluated in the frame of therapeutic approaches over the past 20 years [ 191 , 192 ].…”

Section: Deliverable Recombinant Protein Delivery Mediated By Ptd Tec...mentioning

confidence: 99%

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

et al. 2023

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Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness.

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Strategies for Improving Peptide Stability and Delivery

Cited by 79 publications

References 86 publications

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

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

Identification of multi-targeting natural antiviral peptides to impede SARS-CoV-2 infection

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

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