title: Conformation as the Therapeutic Target for Neurodegenerative Diseases.
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.
authors.affiliation: Proclara Biosciences, 222 Third Street, Cambridge, MA 02142, United States.
authors.forename: Rajaraman
authors.initials: R
authors.lastname: Krishnan
authors.forename: Franz
authors.initials: F
authors.lastname: Hefti
authors.forename: Haim
authors.initials: H
authors.lastname: Tsubery
authors.forename: Michal
authors.initials: M
authors.lastname: Lulu
authors.forename: Ming
authors.initials: M
authors.lastname: Proschitsky
authors.forename: Richard
authors.initials: R
authors.lastname: Fisher
mesh_terms: D000818:Animals; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D018696:Neuroprotective Agents
keywords: Pathophysiology; tauopathies; transcellular propagation; transmissible spongiform encephalopathies.