Skip to main content

New Drug Approvals 2013 - Pt. XXIV - Sofosbuvir (Sovaldi ™)





ATC code (stem): J05AB
Wikipedia: Sofosbuvir
ChEMBL: CHEMBL1259059

On December 6, 2013, the FDA approved sofosbuvir for the treatment of patients with chronic hepatitis C infection. Sofosbuvir is intended for use as a component in combination treatments, depending on the type of hepatitis C either alongside Ribavirin alone, or in combination with both Ribavirin and peginterferon-alpha. Earlier in 2013, the FDA had already approved
Simeprevir for the treatment of this condition.

Hepatitis C is an infectious disease that affects primarily the liver and is caused by the hepatitis C virus (HCV), which belongs to the family of Flaviviridae and has a positive sense single stranded RNA genome of 9,600 nucleotides. Infection is mainly by blood-to-blood contact, through sharing or reuse of syringes or unsterilized medical equipment. Initially, the infection progresses without symptoms, and only becomes apparent in the chronic stages when liver damage leads to symptoms such as bleeding, jaundice, liver cancer and hepatic encephalopathy.

Sofosbuvir is a nucleotide analog inhibitor of the viral RNA polymerase (NS5b, Uniprot genome polyprotein: P26664, 2421-3011, PDB 3hkw). Viral RNA polymerases differ significantly from eukaryotic and bacterial polymerases both in sequence and three-dimensional structure. Thus, sofosbuvir inhibits only the amplification of the viral RNA genome and not endogenous transcription in the host organism by entering the polymerase as a substrate and terminating the transcript chain. The IC50 measured against NS5b ranged between 0.7 and 2.6 micro-molar, depending on the genotpye of the HCV isolate.

Structure of HCV NS5b, genotype 1a generated in pymol from PDB 3hkw.
 Sofosbuvir is a prodrug that is converted to the active form through a mono-phosphorylated intermediate. In contrast to other nucleotide analog inhibitors, the intermediate is formed in a step that cleaves off the groups attached to the phosphate group already present in sofosbuvir. This step is a lot faster than the enzymatic addition of a phosphate group that is required with other nucleotide analogs. The enzymes catalyzing this initial step include the lysosomal protective protein (Uniprot P10619), liver carboxylesterase 1 (Uniprot P23141) and Hint1 (Uniprot P49773). [1]



 Canonical SMILES: CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@](C)(F)[C@@H]1O)Oc3ccccc3 
Std-InChI: InChI=1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1
Std InChI key: TTZHDVOVKQGIBA-IQWMDFIBSA-N

Sofosbuvir is an off-white crystalline substance that is slightly soluble in water. The molecular weight and logP are 529.45 Da and 0.92, respectively. Note the relatively low logP charateristic of nucleotide analog compounds.

The recommended daily dose of sofosbuvir is 400mg in a single tablet. Peak plasma concentration of the active metabolite are reached after 30-120 minutes post administration. The clearance is primarily through the kidney, with a half-life of 0.4 hours for sofosbuvir and 27 hours for its metabolite.  Sofosbuvir is a substrate of P-gp, and therefore inducers of P-gp, such as rifampicin and St John's wort are contraindicated for use with sofosbuvir.

Reported side effects of sofosbuvir include fatigue, headache, nausea, insomnia and anemia.

Sofosbuvir is marketed by Gilead under the name Sovaldi.

References:
[1] Murakami E, Tolstykh T, Bao H, Niu C, Steuer HMM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman P a: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285:34337–47.

Comments

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site:   https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29 .  Please see ChEMBL_29 release notes for full details of all changes in this release: https://ftp.ebi.ac.uk/pub/databases/chembl/ChEMBLdb/releases/chembl_29/chembl_29_release_notes.txt New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no