Synonym
ML-SA1; ML SA1; Mucolipin synthetic agonist 1
IUPAC/Chemical Name
2-[2-(3,4-dihydro-2,2,4-trimethyl-1(2H)-quinolinyl)-2-oxoethyl]-1H-isoindole-1,3(2H)-dione
InChi Key
KDDHBJICVBONAX-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H22N2O3/c1-14-12-22(2,3)24(18-11-7-6-8-15(14)18)19(25)13-23-20(26)16-9-4-5-10-17(16)21(23)27/h4-11,14H,12-13H2,1-3H3
SMILES Code
CC1(C)CC(C)C2=CC=CC=C2N1C(CN3C(C(C=CC=C4)=C4C3=O)=O)=O
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
ML SA1 is an activator of TRPML channels (TRPML1, 2 and 3); does not activate TRPM2, TRPV2, TRPV3, TRPC6 or TRPA1 channels. Induces TRPML-mediated Ca2+ release from lysosomes; activity corrects trafficking defects and reduces cholesterol accumulation in Niemann-Pick type C macrophages.
In vitro activity:
ML-SA1, a TRPML agonist, inhibited DENV2 and ZIKV in vitro in a dose-dependent manner. Time-of-drug-addition experiments showed that ML-SA1 mainly restricted viral entry. Moreover, the selective TRPML3 activator SN-2 was found to share a similar antiviral effect against DENV2 and ZIKV, but the specific TRPML1 agonist MK6-83 was not effective. Although ML-SA1 was further revealed to induce autophagy, its antiviral role was independent of autophagy induction. Finally, ML-SA1 was found to inhibit DENV2 and ZIKV by promoting lysosome acidification and protease activity to cause viral degradation. Together, our study identifies two TRPML agonists, ML-SA1 and SN-2, as potent inhibitors of DENV2 and ZIKV, which may lead to the discovery of new candidates against viruses.
Reference: Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Res. 2020 Oct;182:104922. doi: 10.1016/j.antiviral.2020.104922. Epub 2020 Aug 26. PMID: 32858116.
In vivo activity:
Owning to its potential use in complimenting genetic studies in Drosophila melanogaster to elucidate the cellular and physiological functions of TRPML channels, the effect of ML-SA1 on Drosophila TRPML expressed in HEK293 cells was examind using whole-cell, inside-out, and whole-lysosome electrophysiological recordings. It previously showed that when expressed in HEK293 cells, Drosophila TRPML was localized and functional on both plasma membrane and endolysosome. Here, in both inside-out patches excised from the plasma membrane and whole-lysosome recordings from enlarged endolysosome vacuoles, ML-SA1 failed to activate TRPML unless exogenous phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] was applied. At 1 μM ML-SA1, the sensitivity of TRPML to PI(3,5)P2 increased approximately by 10-fold and at 10 μM ML-SA1, the deactivation of PI(3,5)P2-evoked TRPML currents was markedly slowed. On the other hand, constitutive activation of TRPML by a mutation that mimics the varitint-waddler (Va) mutation of mouse TRPML3 rendered the insect channel sensitive to activation by ML-SA1 alone. Moreover, different from the insect TRPML, mouse TRPML1 was readily activated by ML-SA1 independent of PI(3,5)P2. Thus, our data reveal that while ML-SA1 acts as a true agonist at mouse TRPML1, it behaves as an allosteric activator of the Drosophila TRPML, showing dependence on and the ability to stabilize open conformation of the insect channels.
Reference: Feng X, Xiong J, Lu Y, Xia X, Zhu MX. Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1. Cell Calcium. 2014 Dec;56(6):446-56. doi: 10.1016/j.ceca.2014.09.004. Epub 2014 Sep 19. PMID: 25266962; PMCID: PMC4252876.
|
Solvent |
mg/mL |
mM |
comments |
| Solubility |
| DMSO |
7.3 |
20.00 |
|
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
362.43
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Res. 2020 Oct;182:104922. doi: 10.1016/j.antiviral.2020.104922. Epub 2020 Aug 26. PMID: 32858116.
In vitro protocol:
Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z. ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity. Antiviral Res. 2020 Oct;182:104922. doi: 10.1016/j.antiviral.2020.104922. Epub 2020 Aug 26. PMID: 32858116.
In vivo protocol:
Feng X, Xiong J, Lu Y, Xia X, Zhu MX. Differential mechanisms of action of the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1. Cell Calcium. 2014 Dec;56(6):446-56. doi: 10.1016/j.ceca.2014.09.004. Epub 2014 Sep 19. PMID: 25266962; PMCID: PMC4252876.
1: Somogyi A, Kirkham ED, Lloyd-Evans E, Winston J, Allen ND, Mackrill JJ,
Anderson KE, Hawkins PT, Gardiner SE, Waller-Evans H, Sims R, Boland B, O'Neill
C. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of
the endosomal-autophagic-lysosomal system. J Cell Sci. 2023 Mar
15;136(6):jcs259875. doi: 10.1242/jcs.259875. Epub 2023 Mar 21. PMID: 36825945;
PMCID: PMC10112969.
2: Cunha MR, Do Amaral BS, Takarada JE, Valderrama GV, Batista ANL, Batista JM
Jr, Cass QB, Couñago RM, Massirer KB. (S)-ML-SA1 Activates Autophagy via
TRPML1-TFEB Pathway. Chembiochem. 2024 Nov 18;25(22):e202400506. doi:
10.1002/cbic.202400506. Epub 2024 Aug 12. PMID: 38923811.
3: Xia Z, Ren Y, Li S, Xu J, Wu Y, Cao Z. ML-SA1 and SN-2 inhibit endocytosed
viruses through regulating TRPML channel expression and activity. Antiviral Res.
2021 Nov;195:105193. doi: 10.1016/j.antiviral.2021.105193. Epub 2021 Oct 20.
PMID: 34687820.
4: Xia Z, Wang L, Li S, Tang W, Sun F, Wu Y, Miao L, Cao Z. ML-SA1, a selective
TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and
protease activity. Antiviral Res. 2020 Oct;182:104922. doi:
10.1016/j.antiviral.2020.104922. Epub 2020 Aug 26. PMID: 32858116.
5: Feng X, Xiong J, Lu Y, Xia X, Zhu MX. Differential mechanisms of action of
the mucolipin synthetic agonist, ML-SA1, on insect TRPML and mammalian TRPML1.
Cell Calcium. 2014 Dec;56(6):446-56. doi: 10.1016/j.ceca.2014.09.004. Epub 2014
Sep 19. PMID: 25266962; PMCID: PMC4252876.
