nusinersen   Click here for help

GtoPdb Ligand ID: 9416

Synonyms: ASO-10-27 | Ionis-SMNrx | ISIS 396443 | ISIS-SMNRx | ISIS396443 | Spinraza®
Approved drug
nusinersen is an approved drug (FDA (2016), EMA (2017))
Compound class: Synthetic organic
Comment: Nusinersen (ISIS 396443) is an antisense oligo(ribo)nucleotide (ASO) which induces survival motor neuron (SMN) protein expression from SMN2 genes with the exon 7-skipping mutation [7].
Nusinersen was initially available for use as a designated orphan drug (by the US FDA and EMA), and was the first drug to be fully approved for the treatment of spinal muscular atrophy (SMA).

The sequence contains 2'-O-(2-methoxyethyl) (2'-MOE)-oligoribonucleotides to reduce nuclease degradation and enhance binding affinity towards the complementary RNA. The full sequence is [2'-O-(2-methoxyethyl)](3'-5')(P-thio)(mU-mC-A-mC-mU-mU-mU-mC-A-mU-A-A-mU-G-mC-mU-G-G) as detailed in the INN record for the agent. A full structural rendering using SMILES from Chemspider is available here (CSID:34983394). The sequence for nusinersen is claimed in patent WO2010148249A1 as SEQ ID NO: 1 [1].
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 161
Hydrogen bond donors 23
Rotatable bonds 176
Topological polar surface area 3144.17
Molecular weight 7122.28
XLogP -19.23
No. Lipinski's rules broken 3
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
Canonical SMILES COCCOC1C(OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2OP(=O)(OCC2OC(C(C2O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cc(C)c(nc2=O)N)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)C(OC1n1cnc2c1ncnc2N)COP(=O)(OC1C(COP(=O)(OC2C(COP(=O)(OC3C(COP(=O)(OC4C(COP(=O)(OC5C(COP(=O)(OC6C(COP(=O)(OC7C(COP(=O)(OC8C(CO)OC(C8OCCOC)n8cc(C)c(=O)[nH]c8=O)S)OC(C7OCCOC)n7cc(C)c(nc7=O)N)S)OC(C6OCCOC)n6cnc7c6ncnc7N)S)OC(C5OCCOC)n5cc(C)c(nc5=O)N)S)OC(C4OCCOC)n4cc(C)c(=O)[nH]c4=O)S)OC(C3OCCOC)n3cc(C)c(=O)[nH]c3=O)S)OC(C2OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OC(C1OCCOC)n1cc(C)c(nc1=O)N)S
Isomeric SMILES COCCO[C@@H]1[C@H](OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2OP(=O)(OC[C@H]2O[C@H]([C@@H]([C@@H]2O)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cc(C)c(nc2=O)N)S)OCCOC)n2cnc3c2nc(N)[nH]c3=O)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cnc3c2ncnc3N)S)OCCOC)n2cc(C)c(=O)[nH]c2=O)S)[C@H](O[C@H]1n1cnc2c1ncnc2N)COP(=O)(O[C@@H]1[C@@H](COP(=O)(O[C@@H]2[C@@H](COP(=O)(O[C@@H]3[C@@H](COP(=O)(O[C@@H]4[C@@H](COP(=O)(O[C@@H]5[C@@H](COP(=O)(O[C@@H]6[C@@H](COP(=O)(O[C@@H]7[C@@H](COP(=O)(O[C@@H]8[C@@H](CO)O[C@H]([C@@H]8OCCOC)n8cc(C)c(=O)[nH]c8=O)S)O[C@H]([C@@H]7OCCOC)n7cc(C)c(nc7=O)N)S)O[C@H]([C@@H]6OCCOC)n6cnc7c6ncnc7N)S)O[C@H]([C@@H]5OCCOC)n5cc(C)c(nc5=O)N)S)O[C@H]([C@@H]4OCCOC)n4cc(C)c(=O)[nH]c4=O)S)O[C@H]([C@@H]3OCCOC)n3cc(C)c(=O)[nH]c3=O)S)O[C@H]([C@@H]2OCCOC)n2cc(C)c(=O)[nH]c2=O)S)O[C@H]([C@@H]1OCCOC)n1cc(C)c(nc1=O)N)S
InChI Key WWFDJIVIDXJAQR-FFWSQMGZSA-N
Bioactivity Comments
The molecular defect of this disease derives from a C-to-T transition in an exonic splicing enhancer site which impairs the ability of the spliceosome to recognize exon 7. The molecular mechanism of action of this drug is blocking the intronic splicing silencer of the 5′ region of SMN2 intron 7 (ISS-N1). It thereby promotes exon 7 inclusion and a corresponding increase in full-length SMN2 protein [6].