Narlaprevir

Since the emergence of the coronavirus 2 (SARS-CoV-2), the approach taken to discover new drugs against this virus was to find reliable inhibitors of the main protease (M^pro) leading to minimize its proliferation and its complications observed in patients such as severe acute respiratory syndromes.In this regard, several works have been carried out based on this approach.In this investigation, combined computational studies were performed to examine the inhibitory performance of 12 cannabinoid-derived compounds and 38 terpene-derived compounds against SARS-CoV-2.At the beginning, a mol. docking study was done to predict the types of interactions and binding energies of each studied compound with respect to the active site of the main protease (M^pro).According to the docking results, seven compounds (THCV, CBN, Δ-9-THC, Δ-8-THC, CBC, THCA and CBCA) present high binding energies leading to strong interactions to their target protein. showed also more stable affinity energies than the reference drug, Narlaprevir.Then, the ADME-Tox (absorption, distribution, metabolism, excretion and toxicity) properties of these ligands were evaluated.As results, only one among the selected ligands showed that it could be selected as a potential anti-SARS-CoV-2 candidate.Finally, the binding stability of this compound in the active site of the main protease was confirmed through mol. dynamics simulation which was carried out on a time scale ranging from 0 to 100 ns.

The hepatitis C virus (HCV) poses a great risk to pregnant people and their developing fetus, yet no HCV antiviral treatment guidelines have been established. While there has been a substantial increase in the development of HCV antivirals, the effect they have on the developing fetus remains poorly defined. Many of these drugs are metabolized through the cytochrome P450 CYP3A pathway, which is mediated by cytochrome P450 3A7 (CYP3A7) in the fetus and developing infant. In this study, we sought to investigate the effect HCV antivirals have on CYP3A7 metabolism, as this CYP enzyme plays a vital role in proper fetal and neonatal development. Of the 13 HCV antivirals we investigated, 8 (∼62%) inhibited CYP3A7 metabolic activity by 50% or more at a concentration of 20 µM. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 µM, which is physiologically relevant in comparison with the K_m of dehydroepiandrosterone-sulfate (DHEA-S) oxidation (reported to be between 5 and 20 µM). We also discovered that paritaprevir is a time-dependent inhibitor of CYP3A7, which shifts the IC₅₀ ∼twofold from 11 µM to 5 µM. Upon further characterization, paritaprevir inactivates DHEA-S metabolism by CYP3A7, with K_I and K_inact values of 4.66 µM and 0.00954 minute^-1, respectively. Depending on treatment plan and off-label drug use, HCV treatment could adversely affect the fetal-maternal communication axis by blocking fetal CYP3A7 metabolism of important endogenous hormones. SIGNIFICANCE STATEMENT: The prevalence of HCV in pregnant people is estimated at between 1% and 8% of the global population, yet little to no information exists about the risk antiviral treatment poses to the developing fetus. There is a potential risk of drugs adversely affecting mother-fetal communication by inhibiting fetal hepatic CYP3A7, an integral enzyme for estriol production. We discovered that five HCV antivirals inhibited DHEA-S metabolism by CYP3A7, and paritaprevir inactivated the enzyme. Our studies demonstrate the potential threat these drugs pose to proper fetal development.