Design and Synthesis of Oleanolic Acid Trimers to Enhance Inhibition of Influenza Virus Entry

Abstract

Influenza is a major threat to millions of people worldwide. Entry inhibitors are of particular interest for the development of novel therapeutic strategies for influenza. We have previously discovered oleanolic acid (OA) to be a mild influenza hemagglutinin (HA) inhibitor. In this work, inspired by the 3D structure of HA as a homotrimeric receptor, we designed and synthesized 15 OA trimers with different linkers and central region via the copper-catalyzed azide−alkyne cycloaddition reaction. All of the OA trimers were evaluated for their antiviral activities in vitro, and 12c, 12e, 13c, and 13d were observed to exhibit robust potency (IC 50 in the submicromolar range) against influenza A/WSN/33 (H1N1) virus that was stronger than that observed with oseltamivir. In addition, these compounds also displayed strong biological activity against A/Hong Kong/4801/2014 and B/Sichuan/531/2018 (BV). The results of hemagglutination inhibition assays and surface plasmon resonance binding assays suggest that these OA trimers may interrupt the interaction between the HA protein of influenza virus and the host cell sialic acid receptor, thus blocking viral entry. These findings highlight the utility of multivalent OA conjugates to enhance the ligand− target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products.

Assembly of Poly(ethylene glycol)ylated Oleanolic Acid on a Linear Polymer as a Pseudomucin for Influenza Virus Inhibition and Adsorption

“…Compared with the interaction between the monomer OAPEG and HA ( K D = 117 μM), which showed fast association and dissociation phases (Figure C), the OAPM polymer functioned as a macromolecule with more binding sites to HA and thus showed a stronger binding affinity ( K D = 74 nM) (Table ). Compared with a trivalent OA conjugate with a K D of 2.63 μM and a septavalent OA–cyclodextrin conjugate with a K D of 2.08 μM, our OAPM has the highest OA content on the polymer backbone, which induced a much lower K D value. Similar linear polymers with multivalent presentations of sialyl lactose using chitosan and polynorbornenyl glycine or acrylamide as the backbones have also been reported to achieve higher HA binding activities with K D values around 600 nM.…”

“…In contrast, the polymeric OAPM showed an EC 50 that was over 500 times reduced. Since 138 molecules of OAPEG were loaded onto the polymer backbone, OAPM showed a stronger antiviral activity than trivalent OA and a septavalent OA–cyclodextrin conjugate with EC 50 on a micromolar range. An average of seven times enhancement per one monomer was achieved, again confirming that the multivalent presentation can dramatically enhance the protein–ligand binding affinity. , All these results were consistent with the SPR, ITC, and HAI assays.…”

C3-Symmetric Ligands in Drug Design: When the Target Controls the Aesthetics of the Drug

“…The tripodal core of these inhibitors mainly contains a trisubstituted benzene ring, displaying glycan moieties in the three binding sites of the trimeric hemagglutinin. Alternatively, oleanic acid, a pentacyclic triterpene, can replace the glycans to inhibit the protein–protein interaction between hemagglutinin and sialic acid [ 39 ]. Glycan and oleanic acid moieties are often introduced on the benzene tripodal core using click chemistry and triazole formation.…”

Synthesis and biological activity of potential antiviral compounds through 1,3-dipolar cycloadditions; Part 1: general aspects and reactions of azides

“…These findings highlight the utility of multivalent OA conjugates to enhance the ligand−target interactions in anti-influenza virus drug design and are also helpful for studying antiviral drugs derived from natural products. 117 Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-L-ascorbic acid derivatives with the hydroxyethylene and ethylidene linkers were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. The conformationally unrestricted spacer between the lactone and 1,2,3-triazole units had a great effect on antitumor activity.…”