Simeprevir 150mg capsules

Abstract Context: Chronic hepatitis C virus (HCV) infection is associated with thyroid dysfunction, historically linked to interferon-based therapies. The impact of direct-acting antivirals (DAAs) on thyroid function remains controversial. Objective: To assess the prevalence and evolution of thyroid dysfunction in HCV-infected patients treated with DAAs through a systematic review with quantitative synthesis where feasible. Methods: A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and LILACS, without language restrictions, from January 2000 through October 2025, using the following terms: ("hepatitis C" OR "HCV") AND ("thyroid disease" OR "hypothyroidism" OR "hyperthyroidism" OR "thyroiditis") AND ("direct-acting antivirals" OR "DAA" OR "sofosbuvir" OR "ledipasvir" OR "daclatasvir" OR "simeprevir" OR "velpatasvir"). A random-effects meta-analysis of baseline prevalence was performed for three studies with complete extractable data (n=13,915); one study was excluded due to methodological overlap and incomplete denominators. Results: Four studies (n = 14,016) met inclusion criteria. Baseline prevalence of thyroid dysfunction ranged from 13.3% to 24.6%. Quantitative synthesis yielded a pooled prevalence estimate of 19.0% (95% CI: 9.6–30.8%), with substantial heterogeneity (I² = 97.1%). DAA-only regimens did not induce new-onset thyroid dysfunction or autoimmunity. Following sustained virologic response (SVR), 54.5–80% of patients with pre-existing thyroid abnormalities demonstrated improvement or normalization of thyroid function. SVR rates exceeded 95%, irrespective of baseline thyroid status. Conclusion: DAAs exhibit an excellent thyroid safety profile. Despite the high baseline prevalence of thyroid dysfunction among HCV-infected individuals, there is no evidence that DAA therapy induces new thyroid abnormalities; rather, functional improvement is frequently observed after virologic cure.

Abstract licence: CC BY

Members of the solute carrier organic anion transporting polypeptide (OATPs) family function as transporters for a large variety of amphipathic organic anions including endogenous metabolites and clinical drugs, such as bile salts, steroids, thyroid hormones, statins, antibiotics, antivirals, and anticancer drugs. OATP1B1 plays a vital role in transporting such substances into the liver for hepatic clearance. FDA and EMA recommend conducting in vitro testing of drug-drug interactions (DDIs) involving OATP1B1. However, the structure and working mechanism of OATPs still remains elusive. In this study, we determined cryo-EM structures of human OATP1B1 bound with representative endogenous metabolites (bilirubin and estrone-3-sulfate), a clinical drug (simeprevir), and a fluorescent indicator (2',7'-dichlorofluorescein), in both outward- and inward-open states. These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.

Abstract licence: CC BY

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV.

Abstract licence: CC BY

The ability to adjust conformations in response to the polarity of the environment, i.e. molecular chameleonicity, is considered to be important for conferring both high aqueous solubility and high cell permeability to drugs in chemical space beyond Lipinski's rule of 5. We determined the conformational ensembles populated by the antiviral drugs asunaprevir, simeprevir, atazanavir and daclatasvir in polar (DMSO-d6 ) and non-polar (chloroform) environments with NMR spectroscopy. Daclatasvir was fairly rigid, whereas the first three showed large flexibility in both environments, that translated into major differences in solvent accessible 3D polar surface area within each conformational ensemble. No significant differences in size and polar surface area were observed between the DMSO-d6 and chloroform ensembles of these three drugs. We propose that such flexible compounds are characterized as "partial molecular chameleons" and hypothesize that their ability to adopt conformations with low polar surface area contributes to their membrane permeability and oral absorption.

Abstract licence: CC BY-NC

Breast cancer alone accounts for the majority of cancer deaths among women, with the most commonly diagnosed subtype being estrogen receptor positive (ER+). Survival has greatly improved for patients with ER+ breast cancer, due in part to the development of antiestrogen compounds, such as tamoxifen. While treatment of the primary disease is often successful, as many as 30% of patients will experience recurrence and metastasis, mainly due to developed endocrine therapy resistance. In this study, we discovered two tamoxifen combination therapies, with simeprevir and VX-680, that reduce the tumor burden in animal models of ER+ breast cancer more than either compound or tamoxifen alone. Additionally, these tamoxifen combinations reduced the expression of HER2, a hallmark of tamoxifen treatment, which can facilitate acquisition of a treatment-resistant phenotype. These combinations could provide clinical benefit by potentiating tamoxifen treatment in ER+ breast cancer.

Abstract licence: CC BY