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Sofosbuvir, Ribavirin, & Ledipasvir How it Works ?

Sofosbuvir -- the $11B USD Hired Hand The first component in the cocktail is Sofosbuvir, a compound that interferes with the RNA polymerase that the virus uses to replicate itself.  The compound was under development by Princeton, New Jersey Pharmasset, Inc. from 1998 to 2011. In many ways Sofosbuvir is similar to past experimental drugs that essentially mimic a ribonucleotide, selectively stalling the production of viral RNA.  The problem with past drugs was that the creation of triphosphate variants -- a necessity to make the drug usable by the viral polymerase -- was way too slow.

Normally that phosphate would be too reactive, but Pharmasset protected it with an anisole (see the benzene ring) derived side chain and an alanine derive second side chain bonded to the phosphate on the amino end.  In the cell, enzyme strip away these protection molecules quicky.  The naked phosphate has skipped the slow step and transforms into a triphosphate quickly.  But when used by the viral polymerase the fluorine (in place of a hydrogen) clogs up and "breaks" the transcription process.  

Ribavirin, the Tried-and-True Multipurpose Veteran The second component of Solvadi is a guanosine analog called Ribavarin, in which the fused ring responsible for base-pair bonding is broken.  

Ribvarin suffers from the problem mentioned above that Sofosbuvir aimed to solve -- it has no bonded phosphate.  While that allows for a simpler (read: cheaper) molecule, it also makes it act much slower. Nonetheless, Ribavarin has showed itself as a useful treatment against a wide variety of RNA and DNA viruses, plus against certain cancersRibavarin is produced by a number of companies in various countries, and has been used since the 1970s.  However, by itself it's not terrible affective in combatting chronic Hepatitis C.

Ledipasvir -- The New "Secret Sauce" of Solvadi But the secret sauce of Solvadi is Ledipasvir, a massive, bizarre manmade concoction.  How exactly Gilead devised this massive molecule is anyone's guess, but a solid bet would be a lot of modeling and a lot of trial and error. The molecule appears to mimick certain small protein factors and inhibits HCV NS5A, a crucial Heptatitis C protein.  HCV NS5A is thought to be the boss protein of sorts, controlling where Hepatitis C hides in cells, when it chooses to go active, and recruiting the NS5B protein -- Hepatitis C's RNA polymerase -- to replicate the viral Ledipasvir, is the complicated third component for Solvadi.  It interferes with a key Hepatitis C protein. [Image Source: Wikimedia Commons] Gilead's massive compound interferes directly with the protein.  By killing the boss, it delivers a fatal blow to viruses.  It might not always work, but combined with Sofosbuvir, it's a deadly duo.  The Ribavirin just adds to the fracas, further punishing the hapless Ledipasvir interferes with the 5A factor, a "boss protein" that tells Hepatitis C proteins how to act inside a cell. [Image Source: Virology]

Together this trio -- one modestly effective legacy drug, one moderately and highly effective modern drug purchased from a third party, and one massive in-house-created bizarre superdrug -- can kill virtually any Hepatitis C infection.
3 Responses
4806014 tn?1424505478
When I cut and paste part of this article it did not include the source information that I included. Cut & paste gets tricky sometimes.  The article was written by Dailytech.com.  
Avatar universal
The trials I've seen especially for someone in my shoes gt 1a, TT, & experienced have shown Sofosbuvir + Ledipasvir to be more effective without the Ribivirin.  
Avatar universal
In simple terms...per Sovaldi rep:

Think of the HVC cell strand as a string of pearls.
The Sovaldi "cuts" the cell strand holding the pearls.
The Riba attacks the free floating cells.  

Sorry...this is what she said...very simple...but a good visual.  

I have been on it for 3 weeks....non-responder to all other protocol...allergic to interferon....geno 1....ESLD Stage 4 on transplant list so I am hoping this is working no matter if the explanation is complex or simple. I don't have time to wait until the end of the year for another combo.....may still have to do if this doesn't work....but crossing my fingers.....attitude is everything.
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