Martins2013 - True and apparent inhibition of amyloid fribril formation

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Short description
Martins2013 - True and apparent inhibition of amyloid fribril formation

This model is described in the article:

Martins PM.
Prion 2013 Mar-Apr; 7(2): 136-139

Abstract:

A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process.

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Format
SBML (L2V4)
Related Publication
  • True and apparent inhibition of amyloid fibril formation.
  • Martins PM
  • Prion , 0/ 2013 , Volume 7 , pages: 136-139
  • ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. pmmartins@icbas.up.pt
  • A possible therapeutic strategy for amyloid diseases involves the use of small molecule compounds to inhibit protein assembly into insoluble aggregates. According to the recently proposed Crystallization-Like Model, the kinetics of amyloid fibrillization can be retarded by decreasing the frequency of new fibril formation or by decreasing the elongation rate of existing fibrils. To the compounds that affect the nucleation and/or the growth steps we call true inhibitors. An apparent inhibition mechanism may however result from the alteration of thermodynamic properties such as the solubility of the amyloidogenic protein. Apparent inhibitors markedly influence protein aggregation kinetics measured in vitro, yet they are likely to lead to disappointing results when tested in vivo. This is because cells and tissues media are in general much more buffered against small variations in composition than the solutions prepared in lab. Here we show how to discriminate between true and apparent inhibition mechanisms from experimental data on protein aggregation kinetics. The goal is to be able to identify false positives much earlier during the drug development process.
Contributors
Audald Lloret i Villas

Metadata information

is
BioModels Database MODEL1412110000
BioModels Database BIOMD0000000561
isDerivedFrom
BioModels Database BIOMD0000000531
isDescribedBy
PubMed 23232498
hasTaxon
Taxonomy Homo sapiens
isVersionOf
Gene Ontology amyloid fibril formation
hasProperty
Human Disease Ontology Parkinson's disease
Human Disease Ontology Alzheimer's disease
Human Disease Ontology prion disease
Curation status
Curated
  • Model originally submitted by : Audald Lloret i Villas
  • Submitted: 11-Dec-2014 15:28:29
  • Last Modified: 08-Apr-2016 18:52:20
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 08-Apr-2016 18:52:20
    • Submitted by: Audald Lloret i Villas
    • With comment: Current version of Martins2013 - True and apparent inhibition of amyloid fribril formation
  • Version: 1 public model Download this version
    • Submitted on: 11-Dec-2014 15:28:29
    • Submitted by: Audald Lloret i Villas
    • With comment: Original import of Martins2013 - True and apparent inhibition of amyloid fribril formation
Curator's comment:
(added: 11 Dec 2014, 15:36:40, updated: 11 Dec 2014, 15:36:40)
Figure 1a of the reference publication has been reproduced here: Inhibition of amyloid fibrillization as predicted by the Crystallization-like model (CLM) for sigmoidal aggregation kinetics. Black curve represent the normalized fibril mass increase as a function of time (20 arbitrary units). Blue and red curves represent the inhibition of the nucleation and growth steps (true inhibition), respectively; green curve represent the apparent inhibition. The variation of parameters relatively to the normalized mass increase is indicated in the legend. The simulation was done using Copasi v4.14 (Build 89) and the plots were generated using Gnuplot. The Copasi file of the model with simulation settings can be downloaded from the below link: