Abstract
Chronic Hepatitis C is a global health threat and a silent killer. Regardless of the profound progress in preventing and treating this disease, research continues to discover new direct antiviral agents (DAAs), especially against novel targets. Our research has been directed to leverage the NS4A binding site to develop peptidomimetic inhibitors of the hepatitis C virus (HCV) NS3 protease. In previous reports, we could provide evidence of tunability of this site by peptide and nonpeptide NS3/4A inhibitors. In this report, we used structure-based techniques to design 1,2,3,4-tetrahydro-1,7-naphthyridine derivative as NS4A core mimics that cover the region between residues Ile-25′ to Arg-28′. The synthetic plan featured the Povarov reaction as an efficient strategy to construct the 1,7-naphthyridine core. Although this reaction has been reported in many literatures, critical assessments for its scope and limitations are scarce. In our work, we found that Povarov was extremely sensitive to alkene and aldehyde reactants. Moreover, using pyridine amines was not as successful as anilines. The most striking results were the lack of stability of compounds during purification and storage. The four compounds that survived the stability problems (1a-1d) did not show significant binding potency with NS3, because their structures were too simple to resemble the originally planned compounds.
Highlights
Hepatitis C virus (HCV) is a silent killer that starts with mild or even no symptoms, but in many cases, it advances to a life-long illness [1]. e HCV, when activated, attacks liver cells through its E2-envelop protein, maneuvers to penetrate the cell membrane and proceeds to disrupt cellular mechanisms, controls genetic expressions, and leverages cellular machinery to replicate [2, 3]
E recent success of newly discovered direct antiviral agents (DAAs) led to a significant decline in HCV-related deaths concomitant to an increase in survival and recovery rate of patients suffering from the high viral count in their blood [7]. e approved DAAs up until now are directed to three targets: substrate-site inhibitor of NS3/4A protease, NS5A, and NS5B [8] (Figure 1)
Conclusions e robustness of the Povarov reaction helped the synthesis of hundreds of medicinally relevant compounds [29]
Summary
Hepatitis C virus (HCV) is a silent killer that starts with mild or even no symptoms, but in many cases, it advances to a life-long illness [1]. e HCV, when activated, attacks liver cells through its E2-envelop protein, maneuvers to penetrate the cell membrane and proceeds to disrupt cellular mechanisms, controls genetic expressions, and leverages cellular machinery to replicate [2, 3]. E approved DAAs up until now are directed to three targets: substrate-site inhibitor of NS3/4A protease, NS5A, and NS5B [8] (Figure 1). We have been interested in exploring NS4A as a target [9, 10], aiming to add more drugs to the DAA arsenal that may curb the increasingly emerging (a). Another important reason for targeting NS4A is that this 54-mer amino acid peptide is a common factor, albeit not structurally or functionally conserved, among all Flaviviridae family. In HCV, this small peptide is a multipurpose tool for HCV maturation and replication. It plays irreplaceable roles in activating the NS3 protein (both protease and RNA helicase functions), curbing host-cell immunological responses, and integrating the NS3 into the endoplasmic reticulum
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
