SM-102 (Synonyms: Lipid H)

SM-102 is a synthetic ionizable amino lipid that has been widely used to combine with other lipids to form lipid nanoparticles ^[1,2]. Administration of luciferase mRNA in SM-102-containing lipid nanoparticles can induce hepatic luciferase expression in mice^[3]. The formulation containing sm-102 has been significantly used to develop lipid nanoparticles for delivery of mRNA based vaccines ^[4.5], as this efficient transfection method based on compressed lipopolysamine coated plasmids has been developed ^[6].

SM-102 addition was effective at blocking IK(erg) in a concentration-dependent fashion with a half-maximal concentration (IC₅₀ ) of 108 µM, a value which is similar to the KD value (i.e., 134 µM) required for its accentuation of deactivation time constant of the current. The hysteretic strength of IK(erg) in response to the long-lasting isosceles-triangular ramp pulse was effectively decreased in the presence of SM-102.

SM-102 (100 µM) diminished the current magnitude further. In MA-10 Leydig cells, the IK(erg) was also blocked by the presence of SM-102. The IC₅₀ value for SM-102-induced inhibition of IK(erg) in MA-10 cells was 98 µM ^[7]. In BV2 microglial cells, the amplitude of the inwardly rectifying K+ current was inhibited by SM-102. The presence of SM-102 concentration-dependently inhibited IK(erg) in endocrine cells (e.g., GH3 or MA-10 cells).

SM-102 has been implicated in the development of myocarditis following covid-19 vaccination ^[8,9]. However, the need remains unmet whether sm-102 exerts any perturbation on the magnitude of transmembrane ionic currents. Since the sizes of IK (IR) and IK (ERG) are widely expressed in cardiac cells ^[10], the inhibitory effect of sm-102 in altering IK (IR) and / or IK (ERG) may potentially participate in the functional activity of cardiac function. These polycationic molecules enter the KIR or kerg channel pore from the intracellular side and block the movement of K + ions through the channel at depolarized potentials, thereby ensuring a longer plateau phase of the cardiac action potential ^[11]. However, to what extent SM-102-mediated perturbations of membrane ionic currents confer their effectiveness against adverse effects of mRNA based vaccines remains to be further delineated.

References:
[1].Sabnis S, Kumarasinghe E S, Salerno T, et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates[J]. Molecular Therapy, 2018, 26(6): 1509-1519.
[2].Hassett K J, Benenato K E, Jacquinet E, et al. Optimization of lipid nanoparticles for intramuscular administration of mRNA vaccines[J]. Molecular Therapy-Nucleic Acids, 2019, 15: 1-11.
[3].Tao W, Davide J P, Cai M, et al. Noninvasive Imaging of Lipid Nanoparticle-Mediated Systemic [4].Delivery of Small-Interfering RNA to the Liver[J]. Molecular Therapy, 2010, 18(9): 1657-1666.
[4]Reichmuth A M, Oberli M A, Jaklenec A, et al. mRNA vaccine delivery using lipid nanoparticles[J]. Therapeutic delivery, 2016, 7(5): 319-334.
[5]Tenchov R, Bird R, Curtze A E, et al. Lipid Nanoparticles─ From Liposomes to mRNA Vaccine Delivery, a Landscape of Research Diversity and Advancement[J]. ACS nano, 2021, 15(11): 16982-17015.
[6]Behr J P, Demeneix B, Loeffler J P, et al. Efficient gene transfer into mammalian primary endocrine cells with lipopolyamine-coated DNA[J]. Proceedings of the National Academy of Sciences, 1989, 86(18): 6982-6986.
[7].Cho H Y, Chuang T H, Wu S N. Effective Perturbations on the Amplitude and Hysteresis of Erg-Mediated Potassium Current Caused by 1-Octylnonyl 8-[(2-hydroxyethyl)[6-oxo-6 (undecyloxy) hexyl] amino]-octanoate (SM-102), a Cationic Lipid[J]. Biomedicines, 2021, 9(10): 1367.
[8]Vidula M K, Ambrose M, Glassberg H, et al. Myocarditis and other cardiovascular complications of the mRNA-based COVID-19 vaccines[J]. Cureus, 2021, 13(6).
[9]Williams C B, Choi J, Hosseini F, et al. Acute myocarditis following mRNA-1273 SARS-CoV-2 vaccination[J]. CJC open, 2021, 3(11): 1410-1412.
[10]Martinson A S, Van Rossum D B, Diatta F H, et al. Functional evolution of Erg potassium channel gating reveals an ancient origin for IKr[J]. Proceedings of the National Academy of Sciences, 2014, 111(15): 5712-5717.
[11]Sung R J, Wu S N, Wu J S, et al. Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced I K1: a simulation study[J]. American Journal of Physiology-Heart and Circulatory Physiology, 2006, 291(6): H2597-H2605.