Site-Specific PEGylation of HR2 Peptides: Effects of PEG Conjugation Position and Chain Length on HIV-1 Membrane Fusion Inhibition and Proteolytic Degradation.
Summary of "Site-Specific PEGylation of HR2 Peptides: Effects of PEG Conjugation Position and Chain Length on HIV-1 Membrane Fusion Inhibition and Proteolytic Degradation."
Peptides derived from the HR1 or HR2 regions of the HIV-1 envelope glycoprotein gp41 have been shown to be effective inhibitors to prevent virus-host cell membrane fusion. These peptide drugs, however, suffer from relatively short plasma half lifes and are susceptible to enzymatic degradation. Modification of peptides/proteins with poly(ethylene glycol) (PEG) is a well established strategy to overcome these limitations. This manuscript presents the results of a systematic study on the influence of the site of PEGylation of HR2 derived peptides as well as of PEG molecular weight on the biological activity and proteolytic stability of these conjugates. Investigation of the fusion inhibitory efficacy of the conjugates in a model cell-cell based assay revealed a loss in activity for the PEGylated peptides as compared to the wild-type HR2-derived peptide. The loss of activity, however, can be minimized by controlling the site of PEGylation, more specifically, by introducing the PEG chain at one of the more central positions along the non-interacting α-helical surface of the peptides. The proteolytic stability of the PEG-peptide conjugates was assessed in a trypsin-based model assay, which revealed an up to 3.4 fold increase in degradation half life that may help to compensate for the lower inhibitory efficacy of the PEG-peptide conjugates as compared to the wild-type peptide. The results of this study underline the power of site-specific PEGylation to improve the stability of peptide/protein drugs while minimizing adverse effects on biological activity.
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Journal Details
This article was published in the following journal.
Name: Bioconjugate chemistry
ISSN: 1520-4812
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22770564
- DOI: http://dx.doi.org/10.1021/bc3002248
Medical and Biotech [MESH] Definitions
Chromosomal Position Effects
The effects on gene expression that depend on the location of a gene with respect to its neighboring genes and region of chromosome. Stable position effects are sequence dependent. Variegated position effects depend on whether the gene is located in or adjacent to HETEROCHROMATIN or EUCHROMATIN.
Position-specific Scoring Matrices
Tabular numerical representations of sequence motifs displaying their variability as likelihood values for each possible residue at each position in a sequence. Position-specific scoring matrices (PSSMs) are calculated from position frequency matrices.
Chromosome Fragile Sites
Specific loci that show up during KARYOTYPING as a gap (an uncondensed stretch in closer views) on a CHROMATID arm after culturing cells under specific conditions. These sites are associated with an increase in CHROMOSOME FRAGILITY. They are classified as common or rare, and by the specific culture conditions under which they develop. Fragile site loci are named by the letters "FRA" followed by a designation for the specific chromosome, and a letter which refers to which fragile site of that chromosome (e.g. FRAXA refers to fragile site A on the X chromosome. It is a rare, folic acid-sensitive fragile site associated with FRAGILE X SYNDROME.)
Site-specific Dna-methyltransferase (cytosine-n(4)-specific)
A DNA-methyltransferase that catalyzes the transfer of a methyl group from S-ADENOSYLMETHIONINE to the exocyclic NH2 group at the 4 position of CYTOSINE.
Glucagon-like Peptides
Peptides derived from proglucagon which is also the precursor of pancreatic GLUCAGON. Despite expression of proglucagon in multiple tissues, the major production site of glucagon-like peptides (GLPs) is the INTESTINAL L CELLS. GLPs include glucagon-like peptide 1, glucagon-like peptide 2, and the various truncated forms.
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