Trends in Pharmacological Sciences
ReviewChemical kinetics for drug discovery to combat protein aggregation diseases
Section snippets
Chemical kinetics and neurodegenerative disorders
Chemical kinetics (i.e., the measurement and analysis of the rates of chemical reactions) is widely applied in the physical and chemical sciences to study reaction mechanisms and their engineering at the molecular level. Such mechanistic information is particularly valuable in the context of the development of therapeutic strategies to combat diseases. Indeed, information about the microscopic processes underlying changes in macroscopic variables are crucial for understanding the mechanism of
Potential therapeutic targets and proposed inhibitors
Increasing experimental evidence indicates that under in vitro conditions the formation of amyloid fibrils from soluble monomers is the consequence of a range of microscopic aggregation processes which involve the formation of a variety of molecular species, as outlined in Figure 1A 10, 22. The appearance of mature fibrils is accompanied by the formation of low molecular weight oligomers and protofibrils, which can be both on-pathway and off-pathway to the fibril formation. Potentially, each of
Challenges in understanding aggregation inhibition mechanisms at the molecular level
In the past 20 years, a picture has emerged in which protein aggregation occurs via a nucleation step which generates small oligomers from a pool of monomeric proteins. Such oligomers are likely to be very reactive and metastable, and to elongate rapidly into protofibrils and fibrils by monomer addition 55, 56. In most cases, however, the aggregation rate is significantly accelerated by secondary nucleation processes, such as fibril fragmentation and surface catalyzed nucleation, which form new
Kinetic analysis of inhibition mechanisms can play a key role in the development and the evaluation of drug-like small molecules
Because of the low binding affinity and the low enthalpy of binding often observed for inhibitor–protein interactions, the conventional experimental methods described above, which have been developed in the context of enzyme inhibition, remain challenging to apply in the study of the inhibition of amyloid formation.
Chemical kinetics, by contrast, offers the possibility of detecting and analyzing even very weak binding events and their effects. In enzymology, kinetics are routinely applied to
Insights into the inhibition of microscopic reactions by chemical kinetic analysis
An example of the potential offered by this approach is shown in Figure 3, where the in vitro kinetics of fibril formation by the prion protein Ure2p in the presence of different concentrations of a molecular chaperone belonging to the Hsp70 family are shown [77]. The chaperone delays fibril formation in a concentration-dependent manner. By applying the chemical kinetic analysis described above, we are able to identify the specific microscopic event inhibited by the molecular chaperone, in this
Concluding remarks
AD and many other neurodegenerative disorders are fatal conditions currently lacking effective pharmaceutical treatment. Therapeutic strategies to target these diseases can be based on the identification of compounds capable of perturbing the multistep aggregation process of peptides and proteins involved in the molecular and cellular pathogenicity of the diseases. Such inhibitors can act via different mechanisms and target different species produced during the aggregation process. For the
Acknowledgments
This work has been supported by the Swiss National Foundation (P.A.) and the Newman Foundation (P.A., T.P.J.K.), The Biotechnology and Biological Sciences Research Council (BBSRC) (T.P.J.K., C.M.D.), Elan Pharmaceuticals (M.V., C.M.D., T.P.J.K.). We thank Professor Adriano Aguzzi (University of Zurich, Switzerland) for useful discussions.
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