Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Abstract

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023)

“…Most notable are incredible new hepatitis C (combination) drugs containing two or three pyrrolidines, namely daclatasvir (approved 7/2015), elbasvir (approved 1/2016), ombitasvir (approved 12/2014), pibrentasvir (approved 8/2017), and velpatasvir (approved 6/2016), as well as pyrrolidine-containing macrocycles glecaprevir (approved 9/2017), grazoprevir (approved 1/2016), and voxilaprevir (approved 7/2017). These drugs represent not only incredible achievements in treating hepatitis C, with these eight drugs approved within only 4 years, but also drug discovery and design at its best . About the same number (seven) of pyrrolidine-containing drugs are approved for cancer treatments.…”