Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PA_N Endonuclease Inhibitors

Abstract

Influenza PA N inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PA N endonuclease based on the hit D,L-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC 50 values ranging from 0.43 to 1.12 μM in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PA N endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PA N inhibitors of influenza viruses.

Viral RNA capping: Mechanisms and antiviral therapy

“…Nowadays, there are three basic ways to implement inhibitors that target the viral RNA capping process: either by binding to functional domains in viral capping enzymes or by using capsnatching proteins to block enzyme activity, [118][119][120][121][122][123][124][125][126][127][128][129][130][131] disrupting cofactors that sustain the structural integrity of capping enzymes, 132,133,135,136 and targeting of crucial host factors exploited by the virus during specific capping stages. 61,134 The first category of inhibitors is predominantly identified through the screening of molecules obstructing binding interactions, [119][120][121] as well as exploring and designing analogs of the methyl donor or its demethylated products to obstruct the S-adenosyl-1-methionine (SAM)-binding site of viral 2′-O MTase.…”

Emerging drug design strategies in anti-influenza drug discovery

“…After analyzing the binding mode of 13 and PA, Song et al. 43 decided to use compound 13 as the privileged fragment, and optimized its structure through the synthesis of a series of novel compounds. Among them, compound 14 showed the strongest inhibitory effect against the IFV H1N1/A/WSN/33 strain, with an EC 50 value of 0.66 μmol/L.…”

Optimization, and biological evaluation of 3-O-β-chacotriosyl betulinic acid amide derivatives as novel small-molecule Omicron

“…A molecular docking study was performed using Discovery Studio 3.0 [ 34 , 35 ]. The 3D crystal structure of SARS-CoV-2 spike glycoprotein was downloaded from RCSB Protein Date Bank ( www.rcsb.org ) using PDB ID of 6VXX, water and glycosyl molecules removed by manual.…”