Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism

Federico, Alessandro Di; Aitella, Ernesto; Sgambato, D.; Savoia, Alfonso; Bartolomeis, Fabio De; Dallio, Marcello; Ruocco, Eleonora; Pezone, Lucia; Abbondanza, Ciro; Loguercio, C.; Astarita, C.

doi:10.1016/s1665-2681(19)31284-0

Cited by 7 publications

(3 citation statements)

References 34 publications

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“…The FRET assay was validated using commercially available inhibitors (asuanaprevir, ciluprevir, danoprevir, and telaprevir) which significantly decreased the activity of the enzyme (Table 1 ). Furthermore, the IC 50 values of commercial inhibitors (such as telaprevir (0.0475 ± 0.0075 µg/mL) and danoprevir (0.0184 ± 0.0036 µg/mL)) obtained in the current study are very close to the IC 50 values (0.0475 µg/mL and 0.0146 µg/mL, respectively) reported elsewhere [ 49 , 50 ] (Table S 3 ). In agreement with previous studies [ 40 , 41 ], the positive control (the pomegranate pericarp extract) significantly inhibited the activity of HCV NS3-NS4A, displaying an IC 50 value of 5.52 ± 0.74 µg/mL (Figure S 4 ).…”

Section: Discussionsupporting

confidence: 88%

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Khan

Rauf

Habib

et al. 2022

BMC Complement Med Ther

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Background Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. Methods The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI–MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. Results Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. Conclusions A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a.

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Section: Discussionsupporting

confidence: 88%

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Khan

Rauf

Habib

et al. 2022

BMC Complement Med Ther

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“…DAAs have been used clinically for several years, and some limitations were reported, including drug-resistance, low efficacy in cirrhotic patients, drug interactions, liver toxicities, HBV reactivation and skin reactions[6,74-77]. Anti-inflammatory/hepatoprotective agents have fewer side effects for the treatment of HCV-induced liver injury, fibrosis, cirrhosis or even HCC, as demonstrated by their long-term use in liver health cares in many Asian countries[77-80].…”

Section: Anti-inflammatory/hepatoprotective Therapy In Hcv Infectionmentioning

confidence: 99%

Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy

Li¹,

Huang²,

Jiang³

et al. 2018

WJG

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Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.

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“…The sensitivity of patch testing appears highest for abacavir HSS (87%) and DRESS (31·6–58%) and lowest for SJS/TEN (20–24%) and AGEP (18%) . The sensitivity also appears to be affected by the investigated drug: it is highest for abacavir, anticonvulsants and beta‐lactam antibiotics (in particular for abacavir, 87%) and amoxicillin (up to 44·4%), and lowest for vancomycin (9·1%), trimethoprim‐sulfamethoxazole (8·6%), macrolides (4·8%), hepatitis C antivirals and cephalosporins (4·4%) . Oral provocation after a negative patch test should be used with caution in patients with SCARs, considering the low sensitivity of patch testing.…”

Section: Causality Assessment Through Clinical In Vivo and Ex Vivo Tmentioning

confidence: 99%

Recent advances in the understanding of severe cutaneous adverse reactions

et al. 2017

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Severe cutaneous adverse reactions (SCARs) encompass a heterogeneous group of delayed hypersensitivity reactions, which are most frequently caused by drugs. Our understanding of several aspects of SCAR syndromes has evolved considerably over the previous decade. This review explores evolving knowledge on the immunopathogenic mechanisms, pharmacogenomic associations, in-vivo and ex-vivo diagnostics for causality assessment and medication cross-reactivity data related to SCAR syndromes. Given the rarity and severity of these diseases, multidisciplinary collaboration through large international, national and/or multicentre networks to collect prospective data on patients with SCAR syndromes should be prioritized. This will further enhance a systematised framework for translating epidemiological, clinical, and immunopathogenetic advances into preventive efforts and improved outcomes for patients.

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Telaprevir may induce adverse cutaneous reactions by a T cell immune-mediated mechanism

Cited by 7 publications

References 34 publications

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease

Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy

Recent advances in the understanding of severe cutaneous adverse reactions

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