PMID- 29147551
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200929
IS  - 2042-8898 (Print)
IS  - 2042-8901 (Electronic)
IS  - 2042-8898 (Linking)
VI  - 7
IP  - 6
DP  - 2017 Dec 6
TI  - Development of proteolytically stable N-methylated peptide inhibitors of 
      aggregation of the amylin peptide implicated in type 2 diabetes.
PG  - 20160127
LID - 10.1098/rsfs.2016.0127 [doi]
LID - 20160127
AB  - Islet amyloid polypeptide, also known as amylin, is the main component of the 
      amyloid deposits present in approximately 90% of people with type 2 diabetes 
      mellitus (T2DM). In this disease, amylin aggregates into multimeric beta-pleated 
      sheet structures which cause damage to pancreatic islet beta-cells. Inhibitors of 
      early-stage amylin aggregation could therefore provide a disease-modifying 
      treatment for T2DM. In this study, overlapping peptides were designed to target 
      the 'binding' region (RLANFLVHSS, residues 11-20) of human amylin, and their 
      effects on amyloid fibril formation were determined by thioflavin-T assay. The 
      first generation peptides showed less than 50% inhibition of aggregation, but a 
      second generation peptide (H(2)N-RGANFLVHGR-CONH(2)) showed strong inhibitory 
      effects on amylin aggregation, and this was confirmed by negative stain electron 
      microscopy. Cytotoxicity studies revealed that this peptide protected human 
      pancreatic 1.4E7 (ECACC 10070102) insulin-secreting cells from the toxic effects 
      of human amylin. Unlike the retro-inverso version of this peptide, which 
      stimulated aggregation, two N-methylated peptides (H(2)N-RGAmNFmLVmHGR-CONH(2) 
      and H(2)N-RGANmFLmVHmR-CONH(2)) gave very clear dose-dependent inhibition of 
      fibril formation. These two peptides were also stable against a range of 
      different proteolytic enzymes, and in human plasma. These N-methylated peptides 
      could provide a novel treatment for slowing progression of T2DM.
FAU - Obasse, Idira
AU  - Obasse I
AD  - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, 
      University of Lancaster, Lancaster LA1 4YQ, UK.
FAU - Taylor, Mark
AU  - Taylor M
AD  - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, 
      University of Lancaster, Lancaster LA1 4YQ, UK.
FAU - Fullwood, Nigel J
AU  - Fullwood NJ
AD  - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, 
      University of Lancaster, Lancaster LA1 4YQ, UK.
FAU - Allsop, David
AU  - Allsop D
AUID- ORCID: 0000-0002-0513-5575
AD  - Division of Biomedical and Life Sciences, Faculty of Health and Medicine, 
      University of Lancaster, Lancaster LA1 4YQ, UK.
LA  - eng
SI  - figshare/10.6084/m9.figshare.c.3876073
PT  - Journal Article
DEP - 20171020
PL  - England
TA  - Interface Focus
JT  - Interface focus
JID - 101531990
PMC - PMC5665791
OTO - NOTNLM
OT  - IAPP
OT  - N-methylated peptide
OT  - amylin
OT  - amyloid
OT  - diabetes
OT  - islet amyloid polypeptide
COIS- We declare we have no competing interests.
EDAT- 2017/11/18 06:00
MHDA- 2017/11/18 06:01
PMCR- 2018/12/06
CRDT- 2017/11/18 06:00
PHST- 2017/11/18 06:00 [entrez]
PHST- 2017/11/18 06:00 [pubmed]
PHST- 2017/11/18 06:01 [medline]
PHST- 2018/12/06 00:00 [pmc-release]
AID - rsfs20160127 [pii]
AID - 10.1098/rsfs.2016.0127 [doi]
PST - ppublish
SO  - Interface Focus. 2017 Dec 6;7(6):20160127. doi: 10.1098/rsfs.2016.0127. Epub 2017 
      Oct 20.