bemnifosbuvir   Click here for help

GtoPdb Ligand ID: 11295

Synonyms: AT-527 | AT527 | RO-7496998 | RO7496998
Compound class: Synthetic organic
Comment: AT-527 is the orally bioavailable hemi-sulfate salt of AT-511, which is a direct-acting antiviral compound that disrupts activity of the viral RNA polymerase [1]. It was originally developed to combat hepatitis C (HCV) infection, but has been redeployed for SARS-CoV-2. Chemically AT-527 is a phosphoramidate purine nucleotide and it is metabolised to a biologically active guanosine triphosphate analogue in vivo. Preclinical results showing pan-genotype activity against HCV were published in early 2020 [2]. In October 2020 anti-SARS-CoV-2 activity was reported in preprint format [3], which converted to full peer reviewed publication in March 2021 [4].

AT-527 was developed by Atea Pharmaceuticals [5]. In October 2020 it was announced that Roche were purchasing the rights to AT-527 (and gave it the research code RO7496998) outside of the US. In the same press release, it was revealed that AT-527 would be evaluated in Phase 3 trial in early 2021 to determine its efficacy as an early treatment for COVID-19 in non-hospitalised patients.

This is a complex molecule with 5 stereo-centres, so there are several CIDs with the same connectivity in PubChem. We chose to represent the molecule from CID 122527275 as it is linked to a FDA UNique Ingredient Identifier (UNII) code. This CID represents the parent molecule. For the hemi-sulfate salt structure see PubChem CID 155926085.
2D Structure
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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.

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Physico-chemical Properties
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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.

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Hydrogen bond acceptors 12
Hydrogen bond donors 4
Rotatable bonds 12
Topological polar surface area 194.78
Molecular weight 581.22
XLogP 2.31
No. Lipinski's rules broken 2
SMILES / InChI / InChIKey
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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.

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Canonical SMILES CNc1nc(N)nc2c1ncn2[C@@H]1O[C@@H]([C@H]([C@@]1(C)F)O)CO[P@@](=O)(N[C@H](C(=O)OC(C)C)C)Oc1ccccc1
Isomeric SMILES C[C@@H](C(=O)OC(C)C)N[P@](=O)(OC[C@@H]1[C@H]([C@@]([C@@H](O1)n1cnc2c(nc(nc12)N)NC)(C)F)O)Oc1ccccc1
InChI InChI=1S/C24H33FN7O7P/c1-13(2)37-21(34)14(3)31-40(35,39-15-9-7-6-8-10-15)36-11-16-18(33)24(4,25)22(38-16)32-12-28-17-19(27-5)29-23(26)30-20(17)32/h6-10,12-14,16,18,22,33H,11H2,1-5H3,(H,31,35)(H3,26,27,29,30)/t14-,16+,18+,22+,24+,40-/m0/s1
InChI Key OISLSHLAXHALQZ-LZEIJKKFSA-N
References
1. Berliba E, Bogus M, Vanhoutte F, Berghmans PJ, Good SS, Moussa A, Pietropaolo K, Murphy RL, Zhou XJ, Sommadossi JP. (2019)
Safety, pharmacokinetics and antiviral activity of AT-527, a novel purine nucleotide prodrug, in HCV-infected subjects with and without cirrhosis.
Antimicrob Agents Chemother, 63 (12). [PMID:31570394]
2. Good SS, Moussa A, Zhou XJ, Pietropaolo K, Sommadossi JP. (2020)
Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus.
PLoS One, 15 (1): e0227104. [PMID:31914458]
3. Good SS, Westover J, Jung KH, La Colla P, Collu G, Moussa A, Canard B, Sommadossi J-P. (2020)
AT-527 is a potent in vitro replication inhibitor of SARS-CoV-2, the virus responsible for the COVID-19 pandemic.
bioRxiv, Preprint. DOI: 10.1101/2020.08.11.242834
4. Good SS, Westover J, Jung KH, Zhou XJ, Moussa A, La Colla P, Collu G, Canard B, Sommadossi JP. (2021)
AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.
Antimicrob Agents Chemother, 65 (4). DOI: 10.1128/AAC.02479-20 [PMID:33558299]
5. Moussa A, Sommadossi J-P. (2018)
Nucleotide hemi-sulfate salt for the treatment of hepatitis c virus.
Patent number: WO2018144640A1. Assignee: Atea Pharmaceuticals, Inc.. Priority date: 01/02/2017. Publication date: 09/08/2018.