Daclatasvir

Daclatasvir ejerce sus efectos antivirales uniéndose al extremo N-terminal dentro del Dominio 1 de la proteína no estructural 5A (NS5A) del VHC. Esta unión inhibe la replicación del ARN viral y el ensamblaje de viriones, evitando eficazmente que el virus se multiplique y se propague . La inhibición de NS5A interrumpe la formación del complejo de replicación viral, lo que lleva a una disminución de la carga viral y a la eliminación final de la infección .

Compuestos similares:

Sofosbuvir: Otro medicamento antiviral que se utiliza en combinación con this compound para tratar el VHC. Inhibe la ARN polimerasa NS5B del VHC.

Ledipasvir: Similar a this compound, inhibe la proteína NS5A, pero tiene diferentes propiedades farmacocinéticas.

Velpatasvir: Otro inhibidor de NS5A con un espectro de actividad más amplio contra varios genotipos de VHC.

Singularidad de this compound: this compound es único debido a su alta selectividad y potencia contra la NS5A del VHC. Tiene un perfil farmacocinético bien caracterizado, lo que permite una administración oral una vez al día. Además, this compound ha demostrado eficacia en pacientes con enfermedad hepática avanzada y en aquellos coinfectados con VIH .

Efficacy in Chronic Hepatitis C Treatment

Clinical Trials and Real-World Studies

• Combination Therapy : Daclatasvir is most commonly used in combination with sofosbuvir and ribavirin. In clinical trials such as the ALLY-1 study, this compound combined with sofosbuvir and ribavirin demonstrated high SVR rates:
  • Genotype 1 : 82% SVR12 in patients with advanced cirrhosis.
  • Genotype 3 : 83% SVR12 for patients with advanced cirrhosis and 95% for post-liver transplantation patients .
• Real-World Effectiveness : Observational studies have shown that this compound plus sofosbuvir achieves cure rates of 90% or higher across various genotypes:
  • For genotype 2: SVR rates were reported at 94.5%.
  • For genotype 3: SVR rates were approximately 90% .

Applications Beyond Hepatitis C

Potential Use in COVID-19 Treatment

Recent studies have explored the use of this compound in treating COVID-19. A meta-analysis indicated that patients treated with this compound and sofosbuvir had significantly lower mortality rates compared to those receiving standard care (5% vs. 20%) and shorter hospital discharge times . This suggests a potential role for this compound as part of therapeutic regimens for COVID-19, particularly in hospitalized patients.

Case Studies

Diverse Patient Populations

• HIV/HCV Coinfection : this compound has shown promise in treating patients with both HIV and HCV, achieving high SVR rates even among those with advanced liver disease .
• Post-Liver Transplant Recipients : In transplant populations, this compound combined with sofosbuvir resulted in SVR rates exceeding 90%, demonstrating its safety and efficacy in this vulnerable group .

Summary of Key Findings

Biochemical Properties

Daclatasvir exerts its antiviral action by preventing RNA replication and virion assembly via binding to NS5A, a nonstructural phosphoprotein encoded by HCV . Binding to the N-terminus of the D1 domain of NS5A prevents its interaction with host cell proteins and membranes required for virion replication complex assembly .

Cellular Effects

This compound has a profound effect on viral load with onset that is more rapid than had been seen previously with either NS3 protease or NS5B polymerase inhibitors . It disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status .

Molecular Mechanism

This compound works by inhibiting the HCV protein NS5A . It targets both the cis- and trans-acting functions of NS5A and disrupts the function of new HCV replication complexes by modulating the NS5A phosphorylation status .

Temporal Effects in Laboratory Settings

This compound undergoes rapid absorption, with a time to reach maximum plasma concentration of 1–2 h and an elimination half-life of 10 to 14 h observed in single-ascending dose studies . Steady state was achieved by day 4 in multiple-ascending dose studies .

Dosage Effects in Animal Models

In-vivo animal studies suggested that this compound concentrates in livers (mice, rats, dogs, and monkeys), with liver-to-serum or liver-to-plasma area under the concentration–time curve (AUC) ratios ranging from 1.9 to 17 in the different animal species tested .

Metabolic Pathways

This compound has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion . Renal clearance is a minor route of elimination for this compound .

Transport and Distribution

This compound is transported and distributed within cells and tissues via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion .

Subcellular Localization

Given its mechanism of action, it is likely to be found in close proximity to the HCV NS5A protein, which is associated with the endoplasmic reticulum membrane where the HCV replication complex is located .

Rutas de síntesis y condiciones de reacción: La síntesis de daclatasvir implica múltiples pasos, comenzando con materiales de partida disponibles comercialmente. . Las condiciones de reacción normalmente implican el uso de disolventes orgánicos, catalizadores y temperaturas controladas para garantizar un alto rendimiento y pureza.

Métodos de producción industrial: La producción industrial de this compound sigue una ruta sintética similar, pero se optimiza para la producción a gran escala. Esto implica el uso de reactores de alta eficiencia, procesos de flujo continuo y estrictas medidas de control de calidad para garantizar la coherencia y el cumplimiento de las normas reglamentarias .

3. Análisis de las reacciones químicas

Tipos de reacciones: this compound se somete a diversas reacciones químicas, que incluyen:

Oxidación: this compound puede oxidarse bajo condiciones específicas, lo que lleva a la formación de derivados oxidados.

Reducción: Las reacciones de reducción pueden modificar los anillos de imidazol u otros grupos funcionales dentro de la molécula.

Sustitución: Las reacciones de sustitución pueden ocurrir en el núcleo bifenilo o en los anillos de imidazol, lo que lleva a la formación de diferentes análogos.

Reactivos y condiciones comunes:

Oxidación: Los agentes oxidantes comunes incluyen el peróxido de hidrógeno y el permanganato de potasio.

Reducción: Se utilizan agentes reductores como el borohidruro de sodio y el hidruro de aluminio y litio.

Sustitución: Se emplean varios agentes halogenantes y nucleófilos para las reacciones de sustitución.

Principales productos formados: Los principales productos formados a partir de estas reacciones incluyen derivados oxidados, análogos reducidos y compuestos sustituidos con propiedades farmacológicas modificadas .

Types of Reactions: Daclatasvir undergoes various chemical reactions, including:

Oxidation: this compound can be oxidized under specific conditions, leading to the formation of oxidized derivatives.

Reduction: Reduction reactions can modify the imidazole rings or other functional groups within the molecule.

Substitution: Substitution reactions can occur at the biphenyl core or the imidazole rings, leading to the formation of different analogs.

Common Reagents and Conditions:

Oxidation: Common oxidizing agents include hydrogen peroxide and potassium permanganate.

Reduction: Reducing agents such as sodium borohydride and lithium aluminum hydride are used.

Substitution: Various halogenating agents and nucleophiles are employed for substitution reactions.

Major Products Formed: The major products formed from these reactions include oxidized derivatives, reduced analogs, and substituted compounds with modified pharmacological properties .

Sofosbuvir: Another antiviral medication used in combination with daclatasvir for treating HCV. It inhibits the HCV RNA polymerase NS5B.

Ledipasvir: Similar to this compound, it inhibits the NS5A protein but has different pharmacokinetic properties.

Velpatasvir: Another NS5A inhibitor with a broader spectrum of activity against various HCV genotypes.

Uniqueness of this compound: this compound is unique due to its high selectivity and potency against HCV NS5A. It has a well-characterized pharmacokinetic profile, allowing for once-daily oral administration. Additionally, this compound has shown efficacy in patients with advanced liver disease and those co-infected with HIV .

Daclatasvir (trade name Daklinza) is a direct-acting antiviral agent primarily used in the treatment of hepatitis C virus (HCV) infections. It acts as an inhibitor of the NS5A protein, which is crucial for viral replication and assembly. This article discusses the biological activity of this compound, including its mechanism of action, efficacy in clinical settings, and emerging research related to its antiviral properties against other viruses such as SARS-CoV-2.

This compound functions by binding to the N-terminus of the NS5A protein, inhibiting both viral RNA replication and the assembly of new virions. This mechanism is pivotal in reducing the viral load in infected patients and contributes to the overall effectiveness of HCV treatment regimens.

Clinical Trials and Studies

This compound has demonstrated potent pangenotypic activity against various HCV genotypes (1-4). In clinical trials, it has been shown to significantly improve sustained virological response (SVR) rates when used in combination with other antiviral agents such as sofosbuvir and ribavirin. Key findings from notable studies include:

• COMMAND Trials : These phase 2 trials indicated high SVR rates among patients treated with this compound combined with peginterferon-alpha and ribavirin .
• ALLY Studies : In all-oral combinations, this compound plus sofosbuvir yielded superior response rates, particularly in patients with advanced liver disease and those co-infected with HIV .

Table 1: Summary of Clinical Trial Results for this compound

Antiviral Activity Against SARS-CoV-2

Recent studies have explored the potential of this compound in treating COVID-19. Research indicates that this compound exhibits antiviral activity against SARS-CoV-2, albeit at higher concentrations compared to its efficacy against HCV.

In Vitro Studies

In laboratory settings, this compound showed inhibition of SARS-CoV-2 replication in various cell lines:

• Potency : this compound inhibited viral replication with effective concentrations (EC50) ranging from 0.6 to 1.1 μM in Vero, HuH-7, and Calu-3 cells .
• Mechanism : It was found to favorably alter the folding of secondary RNA structures in the SARS-CoV-2 genome, inhibiting polymerase reactions essential for viral replication .

Table 2: Comparative Potency of this compound Against SARS-CoV-2

Case Studies

Several case studies have documented the use of this compound in patients with chronic HCV and those affected by COVID-19:

• HCV Treatment : A cohort study involving patients with chronic HCV genotype 3 showed a marked improvement in liver function tests and viral load reduction after treatment with this compound combined with sofosbuvir.
• COVID-19 Treatment : In a small case series, patients treated with a combination of this compound and sofosbuvir exhibited reduced symptom severity and shorter recovery times compared to standard care .