In addition to the new emphasis on applying H/D Exchange to the upcoming regulatory issues associated with biogenerics, ExSAR uses the technology to measure drug/protein binding interactions for drug optimization. Subtle changes in protein structure can dramatically affect drug signaling and resistance. H/D Exchange can be applied directly to unlabeled samples of proteins in solution.
H/D Exchange identifies ligand-binding sites on protein targets, determines the structural consequences of ligand binding, and compares the conformations of native and recombinant proteins. Recently, ExSAR determined the interaction subsites for small molecules binding at the active site of p38 MAP kinase, which is drug target associated with inflammation and cancer. The experiments revealed that six subsites on the kinase were altered, and the findings helped to guide the synthesis of new compounds.
Genetic mutations alter protein folding, resulting in reduced protein levels and compromised protein function. A variety of illnesses are attributed to misfolded proteins, including cystic fibrosis; Alzheimer’s, Parkinson’s, and Huntington’s diseases; retinitis pigmentosa; and lysosomal storage disorders such as Tay-Sachs, Gaucher, Pompe, and Fabry’s diseases. Protein misfolding also is linked to prion disorders such as Creutzfeldt-Jakob and mad cow diseases. Structural comparisons of the native and misfolded proteins can identify drugs that promote proper folding or block the misshapen protein.
ExSAR in-licenses compounds to treat rare diseases caused by misfolded proteins. In late 2005, the company licensed NGT (N-acetyl-glucosamine thiazolide) from the Hospital for Sick Children in Toronto. NGT, a small molecule chaperone, controls a vital enzyme associated with adult Tay-Sachs disease. The FDA granted ExSAR Orphan Drug status for NGT. Compounds like NGT represent “a logical progression in a disease area where H/D technology can help to understand how compounds work,” says Dr. Weber.
ExSAR is seeking other compounds related to diseases caused by misfolded proteins. The company plans to advance them through preclinical and early clinical trials, then develop partnerships with larger companies, according to Dr. Almassian. ExSAR also performs contract services for major pharmaceutical and biopharmaceutical companies and biogeneric manufacturers.