Dataset Information

N-PEGylation of a reverse turn is stabilizing in multiple sequence contexts, unlike N-GlcNAcylation.

ABSTRACT: The intrinsic stabilization of therapeutic proteins by N-glycosylation can endow them with increased shelf and serum half-lives owing to lower populations of misfolded and unfolded states, which are susceptible to aggregation and proteolysis. Conjugation of poly(ethylene glycol) (PEG) oligomers to nucleophilic groups on the surfaces of folded proteins (i.e., PEGylation) is a chemical alternative to N-glycosylation, in that it can also enhance the pharmacologic attributes of therapeutic proteins. However, the energetic consequences of PEGylation are currently not predictable. We find that PEGylation of an Asn residue in reverse turn 1 of the Pin WW domain is intrinsically stabilizing in several sequence contexts, unlike N-glycosylation, which is only stabilizing in a particular sequence context. Our thermodynamic data are consistent with the hypothesis that PEGylation destabilizes the protein denatured state ensemble via an excluded volume effect, whereas N-glycosylation-associated stabilization results primarily from native state interactions between the N-glycan and the protein.

SUBMITTER: Price JL

PROVIDER: S-EPMC3220771 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

N-PEGylation of a reverse turn is stabilizing in multiple sequence contexts, unlike N-GlcNAcylation.

Price Joshua L JL Powers Evan T ET Kelly Jeffery W JW

ACS chemical biology 20110922 11

The intrinsic stabilization of therapeutic proteins by N-glycosylation can endow them with increased shelf and serum half-lives owing to lower populations of misfolded and unfolded states, which are susceptible to aggregation and proteolysis. Conjugation of poly(ethylene glycol) (PEG) oligomers to nucleophilic groups on the surfaces of folded proteins (i.e., PEGylation) is a chemical alternative to N-glycosylation, in that it can also enhance the pharmacologic attributes of therapeutic proteins. ...[more]

PMID: 21939258

Similar Datasets

Project description:The association of doublet chemotherapy (FOLFOX and FOLFIRI) and anti-EGFR-moAbs (panitumumab or cetuximab) is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients, especially with left-sided primary tumour. In RAS wt mCRC patients refractory to chemotherapy and anti-EGFR naive, the standard treatment sequence is an anti-EGFR-based therapy (panitumumab or cetuximab +/- irinotecan) followed by regorafenib. In a phase II randomized Japanese study named REVERCE, a higher OS was reported in favour of an experimental strategy of regorafenib followed at progression by cetuximab +/- irinotecan compared with the reverse standard sequence in chemorefractory and anti-EGFR-naïve, RAS wt mCRC patients. However, the limitations of the REVERCE study (phase II trial with a premature conclusion for poor accrual) do not allow us to draw definitive conclusions. In addition, nowadays, patients candidates to an anti-EGFR-based treatment, receive anti-EGFRMoAbs in earlier lines of therapy thus affecting the translation of these results in the current clinical practice. Retrospective analyses and a phase II single-arm trial showed promising activity of anti-EGFR rechallenge in patients who previously achieved benefit from a first-line anti- EGFR-based treatment and not bearing RAS mutation on ct-DNA at the rechallenge baseline. Based on these considerations, the Investigators designed the present phase II randomized study of panitumumab followed at progression by regorafenib versus the reverse sequence in RAS and BRAF wt mCRC patients with the following characteristics: 1. previous treatment with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and an anti-angiogenic agent (bevacizumab or aflibercept); 2. RECIST response or stable disease lasting at least 6 months to a previous first-line anti-EGFR-based treatment; 3. RAS and BRAF wt ct-DNA at the time of screening. The aim of this study is to compare the two sequences in a Caucasian population of patients candidates to anti-EGFR rechallenge.

Dataset Information

N-PEGylation of a reverse turn is stabilizing in multiple sequence contexts, unlike N-GlcNAcylation.

Publications

N-PEGylation of a reverse turn is stabilizing in multiple sequence contexts, unlike N-GlcNAcylation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets