Results from tests of the drug, announced this week, show that it breaks up plaques in mice affected with Alzheimer’s disease or Parkinson’s disease, and improves the memories and cognitive abilities of the animals.
Other promising results in rats and monkeys mean that the drug developers, NeuroPhage Pharmaceuticals, are poised to apply for permission to start testing it in people, with trials starting perhaps as early as next year.
The drug is the first that seems to target and destroy the multiple types of plaque implicated in human brain disease. Plaques are clumps of misfolded proteins that gradually accumulate into sticky, brain-clogging gunk that kills neurons and robs people of their memories and other mental faculties. Different kinds of misfolded proteins are implicated in different brain diseases, and some can be seen within the same condition
How the universal plaque-buster works
A key component of the new plaque-busting drug from NeuroPhage Pharmaceuticals is a protein from a bacteriophage, a type of virus that exclusively infects bacteria. Called M13, the phage was originally isolated from sewage in Germany 50 years ago. Today it is used to screen for antibodies with medical potential. Its plaque-defeating properties were discovered by sheer chance. “It was a total surprise,” says Richard Fisher, chief scientist at NeuroPhage.
The drug is made up of a viral protein that recognises the structural kink that is shared by the misfolded proteins implicated in various brain diseases. This is attached to a fragment of a human antibody. The phage protein binds to the plaques, then the antibody portion marks it for clearance from the brain, says Fisher.
Neurophage’s breakthrough GAIM (general amyloid interaction motif) platform generates therapeutics for the treatment of neurodegenerative diseases and many rare peripheral amyloidoses, all diseases characterized by the accumulation of misfolded proteins.
The lead candidate NPT088 is a fusion protein combining GAIM with a human immunoglobulin Fc region. Each molecule of NPT088 displays two GAIM moieties. NPT088 is a New Molecular Entity (NME) and a first-in-class drug candidate.
Journal of Molecular Biology - A bacteriophage capsid protein provides a general amyloid interaction motif (GAIM) that binds and remodels misfolded protein assemblies.
GAIM–based drugs can simultaneously target multiple misfolded proteins, including several key misfolded intermediates (e.g., small soluble forms and larger pre-existing aggregates that make up brain plaques), that are central factors in many diseases of aging, including Alzheimer’s and Parkinson’s diseases.
The ability of GAIM-based therapy to target key pathological stages of protein misfolding together with the unique ability to target more than one kind of misfolded protein in a given disease maximizes therapeutic potential. For example, NeuroPhage is initially developing NPT088 to treat Alzheimer’s and Parkinson’s diseases, each of which have several misfolded proteins implicated in disease progression.
Neurophage at Alzheimer’s Association International Conference
NeuroPhage Pharmaceuticals, announced that the discovery, preclinical development and clinical trial approach for its lead candidate, NPT088, were highlighted in an oral session at the Alzheimer’s Association International Conference (AAIC) taking place July 18–23, 2015, in Washington, D.C. NPT088 contains the general amyloid interaction motif (GAIM), which allows the compound to universally recognize and disrupt the shape of misfolded proteins and target them for degradation through the body’s natural mechanisms. In the data presented at AAIC, administration of NPT088 led to broad beneficial effects in animal models of Alzheimer’s and Parkinson’s diseases, with improvements in memory and cognition and reductions in toxic protein aggregates.Abstract
Misfolded protein aggregates, characterized by a canonical amyloid fold, play a central role in the pathobiology of neurodegenerative diseases. Agents that bind and sequester neurotoxic intermediates of amyloid assembly, inhibit the assembly or promote the destabilization of such protein aggregates are in clinical testing. Here, we show that the gene 3 protein (g3p) of filamentous bacteriophage mediates potent generic binding to the amyloid fold. We have characterized the amyloid binding and conformational remodeling activities using an array of techniques, including X-ray fiber diffraction and NMR. The mechanism for g3p binding with amyloid appears to reflect its physiological role during infection of Escherichia coli, which is dependent on temperature-sensitive interdomain unfolding and cis-trans prolyl isomerization of g3p. In addition, a natural receptor for g3p, TolA-C, competitively interferes with Aβ binding to g3p. NMR studies show that g3p binding to Aβ fibers is predominantly through middle and C-terminal residues of the Aβ subunit, indicating β strand-g3p interactions. A recombinant bivalent g3p molecule, an immunoglobulin Fc (Ig) fusion of the two N-terminal g3p domains, (1) potently binds Aβ fibers (fAβ) (KD=9.4nM); (2); blocks fAβ assembly (IC50~50nM) and (3) dissociates fAβ (EC50=40-100nM). The binding of g3p to misfolded protein assemblies is generic, and amyloid-targeted activities can be demonstrated using other misfolded protein systems. Taken together, our studies show that g3p(N1N2) acts as a general amyloid interaction motif.
SOURCES - Neurophage Pharma, New Scientist, Journal of Molecular biology