Celgosivir, in development by Migenix for the treatment of
hepatitis C virus
The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus of the family '' Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer (hepatoc ...
(HCV) infection, is an oral
prodrug of the natural product
castanospermine
Castanospermine is an indolizidine alkaloid first isolated from the seeds of ''Castanospermum australe''. It is a potent inhibitor of some glucosidase enzymes and has antiviral activity ''in vitro'' and in mouse models.
The castanospermine deri ...
that inhibits
alpha-glucosidase
α-Glucosidase (EC 3.2.1.20, maltase, glucoinvertase, glucosidosucrase, maltase-glucoamylase, α-glucopyranosidase, glucosidoinvertase, α-D-glucosidase, α-glucoside hydrolase, α-1,4-glucosidase, α-D-glucoside glucohydrolase; systematic n ...
I, an enzyme that plays a critical role in viral maturation by initiating the processing of the N-linked
oligosaccharides
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple suga ...
of viral envelope
glycoproteins
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosy ...
. Celgosivir is well absorbed ''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
'' and ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'', and is rapidly converted to castanospermine. Celgosivir has a novel
mechanism of action
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targ ...
(preventing the glycosylation of viral proteins by the host), and demonstrates broad antiviral activity ''in vitro''.
Clinical trials
Celgosivir is not efficient as a monotherapy for the treatment of HCV, but has demonstrated a synergistic effect in combination with
pegylated interferon alfa-2b plus
ribavirin
Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, pe ...
, both ''in vitro'' and in phase II clinical trials that last up to 1 year in patients with chronic HCV infection. Celgosivir may prove to be a valuable component for combination therapy and may help to prevent the apparition of drug resistance. Long-term toxicity studies are necessary to confirm the safety of celgosivir in humans.
[
Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue fever.]
References
{{reflist
External links
KEGG DRUG: Celgosivir Hydrochloride
Antiviral drugs
Iminosugars
Butyrate esters
Triols
Indolizidines