PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 11763160

Pramlintide (Amylin).

D Barlocco
View original source ↗Export metadata ↓

Abstract

Pramlintide is a human amylin analog, under development by Amylin (originally in collaboration with Johnson & Johnson), as an adjunct with insulin for the potential prevention of complications of type I diabetes, and as a single agent for type II diabetes [279804], [295121], [305454]. In December 2000, Amylin submitted a US NDA seeking approval to market pramlintide as an adjunctive therapy for type 1 and 2 diabetics using insulin [392527]; the application was accepted for review by the FDA in January 2001 [396938], and was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee on July 26 2001 [408924]. In May 2001, Amylin submitted an MAA for pramlintide to the EMEA [411323] and in October 2001, Amylin received an approvable letter from the FDA for both Type I and insulin-using Type II diabetes; however, at this time, discussions with the FDA were ongoing regarding additional clinical work that was required before the NDA would be approved [425570].

Explore related subjects

AmyloidAnimalsDiabetes MellitusHumansHypoglycemic AgentsIslet Amyloid PolypeptideJournal ArticleReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

D Barlocco. 2001. Pramlintide (Amylin).. https://pubmed.ncbi.nlm.nih.gov/11763160/

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2007

Destabilization of transthyretin by pathogenic mutations in the DE loop.

Transthyretin single-amino-acid variants are responsible for familial amyloidotic polyneuropathy, in which transthyretin variants accumulate extracellularly in the form of fibrillar aggregates. We studied the structural stabilities of four transthyretin variants (L58H, L58R, T59K, and E61K), in which a positively charged amino acid is introduced in a loop region between the D- and E-strands. In addition to being located in the DE-loop, L58 and T59 are involved in the core of the transthyretin monomer. The L58H, L58R, and T59K substitutions destabilized transthyretin more than the E61K mutation did, indicating that transthyretin is substantially destabilized by the substitution of residues located in both the DE-loop and the monomer core. By utilizing hydrogen-deuterium exchange and nuclear magnetic resonance, we demonstrated that residues in the G-strand and the loop between the A- and B-strands were destabilized by these pathogenic mutations in the DE loop. At the quaternary structural level, the DE-loop mutations destabilized the dimer-dimer contact area, which may lead to transient dissociation into a dimer. Our results suggest that the destabilization of the dimer-dimer interface and the monomer core is important for the amyloidogenesis of transthyretin.

Amyloid↗
PubMed2007

Formation of amyloid-like fibrils by ovalbumin and related proteins under conditions relevant to food processing.

Protein aggregation is important in food processing, and this work investigated the aggregation of food proteins as a source of amyloid fibrils for use in bionanotechnology. Both purified and crude mixtures of albumin proteins were denatured by heat, which caused aggregation to occur. Protein denaturation was measured by using circular dichroism spectrometry and by following thioflavin T fluorescence, which is widely used as a diagnostic test for amyloid formation. There was a good correlation between the increase in thioflavin T fluorescence and loss of helical structure as the temperature was increased. Formation of thioflavin T fluorescence was dependent on temperature, but less dependent on salt and protein concentration. X-ray fiber diffraction patterns of denatured bovine serum albumin suggested that the protein had a similar cross-beta structure to that of amyloid fibrils. These results are consistent with the aggregates seen during food processing, being amyloid-like in nature.

Amyloid↗
PubMed2007

Nonpolar substitution at the C-terminus of the prion protein, a mimic of the glycosylphosphatidylinositol anchor, partially impairs amyloid fibril formation.

In contrast to most amyloidogenic proteins or peptides that do not contain any significant posttranslational modifications, the prion protein (PrP) is modified with either one or two polysaccharides and a GPI anchor which attaches PrP to the plasma membrane. Like other amyloidogenic proteins, however, PrP adopts a fibrillar shape when converted to a disease-specific conformation. Therefore, PrP polymerization offers a unique opportunity to examine the effects of biologically relevant nonpeptidic modifications on conversion to the amyloid conformation. To test the extent to which a long hydrophobic chain at the C-terminus affects the intrinsic amyloidogenic propensity of PrP, we modified recombinant PrP with an N-myristoylamidomaleimidyl group, which can serve as a membrane anchor. We show that while this modification increases the affinity of PrP for the cell membrane, it does not alter the structure of the protein. Myristoylation of PrP affected amyloid formation in two ways: (i) it substantially decreased the extent of fibrillation, presumably due to off-pathway aggregation, and (ii) it prohibited assembly of filaments into higher order fibrils by preventing their lateral association. The negative effect on lateral association was abolished if the myristoylated moiety at the C-terminus was replaced by a polar group of similar size or by a hydrophobic group of smaller size. When preformed PrP fibrils were provided as seeds, myristoylated PrP supported fibril elongation and formation of higher order fibrils composed of several filaments. Our studies illustrate that, despite a bulky hydrophobic moiety at C-terminus, myristoylated PrP can still incorporate into fibrillar structure and that the C-terminal hydrophobic substitution does not affect the size of the proteinase K resistant core but controls the mode of lateral assembly of filaments into higher order fibrils.

Amyloid↗