Journal of Medicinal Chemistry pubs.acs.org/jmc Article Figure 1. Identification of novel sialin inhibitors (A) structures (2 to 10) of the best hits from a previous virtual screening.33 (B) Whole-cell assay of human sialin. Mutation of its lysosomal sorting motif redirects sialin to the plasma membrane to facilitate transport measurements. (C) Human 3 sialin was assayed for [ H]Neu5Ac uptake at pH 5.0 in the absence (control) or presence of these compounds (means ± SEM of two to four independent experiments). severity. While ISSD affects multiple organs from birth, causing The pathophysiology of Salla disease remains poorly death within a few months or years, Salla disease selectively understood. Sialin-defective mice studies have shown that affects the white matter of the brain in a progressive brain hypomyelination results from defective maturation of 17,20,21 oligodendrocytes.23,24 However, the link between this defect manner. Salla patients show hypotonia, ataxia, nystag- and defective lysosomal sialic acid export or other transport mus, and delayed motor development during the first year. 9 Psychomotor milestones, including speech, progressively activities of sialin (see ref 25) is unclear. Decreased worsen during infancy and childhood, leading to severe downregulation of the polysialylated neural cell adhesion molecule (PSA-NCAM), which could delay oligodendrocyte/ motor and cognitive deficits in adulthood. Magnetic resonance 23 axon contacts, may be involved. However, this decrease is imaging shows nonspecific brain hypomyelination with a limited, indicating that other mechanisms, such as impaired 22 26 thinning of the corpus callosum. Current treatment is ganglioside metabolism, should contribute to the myelination supportive. defect. 8232 https://dx.doi.org/10.1021/acs.jmedchem.9b02119 J. Med. Chem. 2020, 63, 8231−8249