ML SA1 is a selective TRPML agonist with an EC50 value of 15.3μM [1]. The ML SA1 exhibits remarkable antiviral activity, significantly inhibiting the RNA of dengue virus (DENV) and zika virus (ZIKV), with IC50 values of 8.93μM and 52.99μM, respectively[2]. ML SA1 inhibits viral infection by down-regulating the expression of TRPML2 and TRPML3, negatively regulating the expression of the late endosome marker Rab7, and promoting the transport of vesicles from the late endosome to the lysosome[3]. The ML SA1 has been widely used to rescue Alzheimer-related alterations of the endosomal-autophagic-lysosomal system [4].
In vitro, ML SA1 treatment (30μM) for 24 hours significantly increased the expression of LC3-II in NRK-52E cells and promoted autophagy of the cells[5]. Treatment with 25μM ML SA1 for 18 hours significantly reduced the α-synuclein aggregates and protein levels in HEK293T cells[6]. 10μM of ML SA1 pretreatment for 1 hour significantly reduced the production of cleaved caspase-3 in mouse hippocampal neuronal cells induced by oxygen-glucose deprivation (OGD), and decreased the apoptosis rate of neurons[7].
In vivo, ML SA1 treatment via subretinal space injection at a single dose 10μM (5μl) significantly improved retinal structure and the outer nuclear layer, and reduced the apoptosis of photoreceptor cells in a rat model of retinal detachment (RD) [8].
References:
[1] Cunha M R, Do Amaral B S, Takarada J E, et al. (S)‐ML‐SA1 Activates Autophagy via TRPML1‐TFEB Pathway[J]. Chembiochem, 2024, 25(22): e202400506.
[2] Xia Z, Wang L, Li S, et al. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity[J]. Antiviral Research, 2020, 182: 104922.
[3] Xia Z, Ren Y, Li S, et al. ML-SA1 and SN-2 inhibit endocytosed viruses through regulating TRPML channel expression and activity[J]. Antiviral Research, 2021, 195: 105193.
[4] Somogyi A, Kirkham E D, Lloyd-Evans E, et al. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system[J]. Journal of cell science, 2023, 136(6): jcs259875.
[5] Miyano T, Sera T, Sakamoto N. Pharmacological activation of TRPML1 enhances autophagy regulating hypertonicity and TGF-β-induced EMT in proximal tubular epithelial cells[J]. Biochemical and Biophysical Research Communications, 2025, 750: 151432.
[6] Pollmanns M R, Beer J, Rosignol I, et al. Activated endolysosomal cation channel TRPML1 facilitates maturation of α-synuclein-containing autophagosomes[J]. Frontiers in cellular neuroscience, 2022, 16: 861202.
[7] Wang Y, Jiang S, Liu X, et al. Degradation of TRPML1 in neurons reduces neuron survival in transient global cerebral ischemia[J]. Oxidative Medicine and Cellular Longevity, 2018, 2018(1): 4612727.
[8] Yan Y, Wang Y, Ding J, et al. TRPML1 inhibited photoreceptor apoptosis and protected the retina by activation of autophagy in experimental retinal detachment[J]. Ophthalmic research, 2021, 64(4): 587-594.