GS-9256
Source GS-9256 at Peptiology
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Summary
GS-9256 is an oral, phosphinic‑acid‑derived macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. Developed by Gilead Sciences, it has progressed through preclinical testing and early‑phase clinical studies for chronic genotype‑1 HCV infection, often in combination with other direct‑acting antivirals or pegylated interferon‑ribavirin regimens.
Mechanism of Action
GS‑9256 binds to the active site of the HCV NS3/4A protease, blocking the enzyme’s ability to cleave the viral polyprotein. In vitro kinetic studies show a Ki of 89 pM against genotype 1b NS3, rapid association (≈4 × 10⁵ M⁻¹ s⁻¹) and slow dissociation (≈4.8 × 10⁻⁵ s⁻¹). The compound displays >10 000‑fold selectivity over a panel of mammalian proteases, limiting off‑target proteolysis.
What the Research Shows
Biochemical assays demonstrated sub‑nanomolar potency of GS‑9256 against genotype 1 NS3 protease, with reduced activity against genotypes 2a and 3. Cell‑based replicon systems showed EC₅₀ values around 20 nM for genotype 1b, with modest loss of potency for genotype 2a. Preclinical pharmacokinetics revealed high oral bioavailability in mice and moderate exposure in rats, dogs, and monkeys, with primary biliary excretion. Phase I monotherapy in genotype 1 patients produced a mean viral load decline of –3 log₁₀ IU/mL but rapidly selected resistance mutations (R155K, A156V, D168 variants). Phase II combination trials with tegobuvir, ribavirin, and pegylated interferon reported additive antiviral effects, rapid virologic response rates up to 100% in triple‑therapy arms, and transient bilirubin elevations. A genome‑wide association study found no common genetic variants strongly linked to bilirubin rise.
Reported Benefits
GS‑9256 offers potent, highly selective inhibition of the HCV NS3 protease, particularly against genotype 1 strains. Its macrocyclic phosphinic acid scaffold provides favorable pharmacokinetic properties in animal models and enables oral administration. In combination regimens, the drug shows additive or synergistic antiviral activity with other direct‑acting antivirals, ribavirin, and pegylated interferon, leading to high rates of rapid virologic response in early clinical trials.
Limitations of the Evidence
The compound’s potency declines for genotypes 2a and 3, limiting its breadth of coverage. Monotherapy rapidly selects resistance mutations at NS3 positions R155, A156 and D168, which reduce susceptibility. Clinical data are limited to early‑phase studies, and the drug has not achieved regulatory approval. Bioavailability varies across species, and bilirubin elevations have been observed in all treatment groups. Long‑term safety and efficacy remain uncharacterized.
Safety Considerations
Transient elevations in unconjugated bilirubin were reported in all trial arms, but genome‑wide analysis did not identify common genetic predictors. No severe adverse events were highlighted in the abstracts, though the emergence of resistance mutations may compromise treatment durability. As the compound is still investigational, comprehensive safety profiling is pending.
How It Is Administered
GS‑9256 has been administered orally in tablet form in clinical studies, using doses such as 75 mg twice daily, 200 mg twice daily, or 300 mg once daily. The drug is delivered as a systemic oral formulation; no alternative routes have been described in the literature.
Routes of Administration
No administration routes recorded yet.
Goals & Uses
No goal associations recorded yet.
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowBarauskas O, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleLowSheng XC, et al.2012-01-01T00:00:00.000000Z
- Journal ArticleLowNelson D, et al.2014-01-01T00:00:00.000000Z
- Journal ArticleModerateZeuzem S, et al.2012-01-01T00:00:00.000000Z
- Journal ArticleLowYang H, et al.2017-01-01T00:00:00.000000Z
- Journal ArticleModerateMo H, et al.2017-01-01T00:00:00.000000Z
Frequently Asked Questions
What viral target does GS‑9256 inhibit?
GS‑9256 blocks the hepatitis C virus NS3/4A serine protease, an enzyme required for processing the viral polyprotein and essential for viral replication.
Has GS‑9256 been approved for treating hepatitis C?
No. GS‑9256 is an investigational agent that has completed preclinical work and early‑phase clinical trials but has not received regulatory approval for any indication.
Can GS‑9256 be used alone to treat HCV?
Monotherapy showed antiviral activity but quickly selected resistance mutations, suggesting that GS‑9256 is more effective when combined with other antivirals, ribavirin, or pegylated interferon.
Are there any notable side effects?
Transient increases in unconjugated bilirubin have been observed across treatment groups. No other serious adverse events were reported in the available trial data.
How is GS‑9256 taken?
In clinical studies the drug was given as an oral tablet, typically twice daily at doses ranging from 75 mg to 200 mg, or once daily at 300 mg.
What is GS-9256?
GS-9256 is an oral, phosphinic‑acid‑derived macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. Developed by Gilead Sciences, it has progressed through preclinical testing and early‑phase clinical studies for chronic genotype‑1 HCV infection, often in combination with other direct‑acting antivirals or pegylated interferon‑ribavirin regimens.