Review
Chemical kinetics for drug discovery to combat protein aggregation diseases

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Highlights

  • Protein misfolding diseases largely lack effective pharmaceutical treatments.

  • Compounds with the ability to interfere with protein aggregation are attractive drug candidates.

  • The search for inhibitors requires a detailed understanding of the inhibition mechanisms.

  • Chemical kinetic analysis plays a key role in identifying the inhibition mechanisms.

Protein misfolding diseases are becoming increasingly prevalent, yet there are very few effective pharmacological treatments. The onset and progression of these diseases is associated with the aberrant aggregation of normally soluble proteins and peptides into amyloid fibrils. Because genetic and physiological findings suggest that protein aggregation is a key event in pathogenesis, an attractive therapeutic strategy against this class of disorders is the search for compounds able to interfere with this process, in particular by suppressing the formation of soluble toxic oligomeric aggregates. In this review, we discuss how chemical kinetics can contribute to the fundamental understanding of the molecular mechanism of aggregation, and speculate on the implications for the development of therapeutic molecules that inhibit specific steps in the aggregation pathway that are crucial for preventing toxicity.

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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