SAR evolution towards potent C-terminal carboxamide peptide inhibitors of Zika virus NS2B-NS3 protease
Zika virus (ZIKV) is a member of the Flaviviridae family that can cause neurological disorders and congenital malformations.
In an original research publication for the current issue of Frontiers in Neuroscience, IRBM and collaborators developed and applied novel ultrasensitive immunoassays to enable detection of synuclein and S129 phosphorylated synuclein in clinical samples. The new research demonstrated that S129 phosphorylated synuclein is not detectable in cerebrospinal fluid (CSF), while it is readily detectable in plasma.
Phosphorylation at S129 is a post-translational modification associated with the misfolding of SNCA (pS129 SNCA), with the accumulation and aggregation of misfolded SNCA believed to be a cause of Parkinson’s disease. Synuclein and its S129 phosphorylated form may therefore represent key, clinically relevant biomarkers of Parkinson’s disease.
The presence of S129 phosphorylated synuclein in CSF is the subject of considerable debate in the field. While it is known that several groups have failed to detect it in this matrix, the data is unpublished and as yet remains anecdotal. By increasing the detection sensitivity using single-molecule counting technology, we were able to develop an ultrasensitive, quantitative immunoassay for the detection of alpha-synuclein in CSF and plasma. With this new and highly sensitive approach, the study could confirm levels of pS129 in plasma but not in CSF. This provided published experimental evidence for the absence of pS129 in this matrix, at least when measured using a low pg/ml immunoassay.
As pS129 SNCA is reported to be enriched in the plasma of patients with Parkinson’s Disease and is associated with disease specific features, our pS129 SNCA assay can be used to identify and validate pS129 SNCA as a non-invasive biomarker in this neurodegenerative condition.