Conformation as the Therapeutic Target for Neurodegenerative Diseases

Author(s): Rajaraman Krishnan, Franz Hefti, Haim Tsubery, Michal Lulu, Ming Proschitsky, Richard Fisher.

Journal Name: Current Alzheimer Research

Volume 14 , Issue 4 , 2017

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Abstract:

Therapeutic strategies that target pathways of protein misfolding and the toxicity of intermediates along these pathways are mainly at discovery and early development stages, with the exception of monoclonal antibodies that have mainly failed to produce convincing clinical benefits in late stage trials. The clinical failures represent potentially critical lessons for future neurodegenerative disease drug development. More effective drugs may be achieved by pursuing the following two strategies. First, conformational targeting of aggregates of misfolded proteins, rather than less specific binding that includes monomer subunits, which vastly outnumber the toxic targets. Second, since neurodegenerative diseases frequently include more than one potential protein pathology, generic targeting of aggregates by shape might also be a crucial feature of a drug candidate. Incorporating both of these critical features into a viable drug candidate along with high affinity binding has not been achieved with small molecule approaches or with antibody fragments. Monoclonal antibodies developed so far are not broadly acting through conformational recognition. Using GAIM (General Amyloid Interaction Motif) represents a novel approach that incorporates high affinity conformational recognition for multiple protein assemblies, as well as recognition of an array of assemblies along the misfolding pathway between oligomers and fibers. A GAIM-Ig fusion, NPT088, is nearing clinical testing.

Keywords: Pathophysiology, tauopathies, transcellular propagation, transmissible spongiform encephalopathies.

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Article Details

VOLUME: 14
ISSUE: 4
Year: 2017
Page: [393 - 402]
Pages: 10
DOI: 10.2174/1567205014666170116152622
Price: $58

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