Truncated ring-A amaryllidaceae alkaloid modulates the host cell integrated stress response, exhibiting antiviral activity to HSV-1 and SARSCoV-2

Abstract

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.

Unveiling Amaryllidaceae alkaloids: from biosynthesis to antiviral potential – a review

“…Sprekelia formosissima was used [6,10-3 H 2 ; 12-14 C] noroxomaritidine for labelling, which resulted in incorporations of 0.03% into ismine, 2% into haemanthamine, and 0.8% into haemanthidine. Ismine showed no 14 C activity. The radioactive ismine's labelling pattern was indirectly determined by its conversion into phenanthidone, which retained approximately 25% of the tritium activity.…”

“…125,130 7-Hydroxyl derivative trans-dihydrolycoricidine and dihydronarciclasine analog lacking the methylenedioxy group, with a C7-OH on ring-A, and a fully functionalized ring-C (no double bond but 3 hydroxyl in a similar orientation as lycoricidine) efficiently targeted HSV replication, whereas other modications of dihydronarciclasine analog, including hydroxylation or O-methylation of C9, were not active. 13 As both derivatives affected the elF2 pathway involved in protein translation, 14 triggered autophagy and apoptosis-related signalling pathways involving ERK and Sirtuin-1, ring B and C stereocenters appear to be key to their activity. Previous studies by Gabrielsen and Jimenez et al showed that ring C hydroxyls were crucial for antiviral activity and that the C1-C10b double bond was associated with increased cytotoxicity, while C7 deoxy derivatives led to lower cytotoxic properties.…”

“…9 7-Hydroxyl derivative trans-dihydrolycoricidine, and dihydronarciclasine analog with ring-A mono-substituted and C7-OH with fully functionalized ring-C targets herpesvirus replication, 13 affecting eukaryotic initiation factor 2 (elF2) pathway involved in protein translation. 14…”

“…4 Although many recent studies have focused on lycorine, narciclasine and its analogues have been previously shown to be strong inhibitors of coronaviruses and RNA viruses possibly through interaction with eukaryotic translation elongation factors eEF1A, nucleocapsid and/or nucleic acids, as extensively reviewed in. 108 Earlier this year (2023), chemically synthetized trans -dihydrolycoricidine and dihydronarciclasine analog with ring-A mono-substituted C7-OH were also identified as inhibitors of SARS-CoV-2, 14 with IC 50 = 0.18 μM, CC 50 = 3.48 μM, IC 50 = 0.09 μM, and CC 50 = 1.92 μM. Le et al reported that 6α-hydroxyhippeastidine, 6β-hydroxyhippeastidine, 2- epi -lycorine, zephyranthine, and ungeremine isolated from Hymenocallis littoralis demonstrated weak anti-SARS-CoV-2 activity.…”

“…(6) Lycorine C1 and C2 are required to block alphavirus replication through viral RNA translation inhibition 9. 7-Hydroxyl derivative trans-dihydrolycoricidine, and dihydronarciclasine analog with ring-A mono-substituted and C7-OH with fully functionalized ring-C targets herpesvirus replication, 13 affecting eukaryotic initiation factor 2 (elF2) pathway involved in protein translation 14. (7) These derivatives also triggered autophagy and (8), apoptosis-related signaling pathways involving ERK and Sirtuin-1.…”