Selection of influenza virus resistant to the novel camphor-based antiviral camphecene results in loss of pathogenicity

Abstract

Due to the ability of influenza virus to develop drug resistance, the search for novel antivirals is an important goal of medical science and health care systems. We assessed the ability of the influenza virus to develop resistance to the hemagglutinin inhibitor camphecene and characterized laboratory-selected resistant strains. We showed by electron microscopy that camphecene decreases the number of virions fusing their envelopes with endosomal membranes. A 160-fold decrease in virus susceptibility was observed after six passages in cells. This was associated with the emergence of a V458L mutation in the HA2 subunit of HA and with a decrease in viral pathogenicity. Molecular modeling predicts that this substitution results in a more stable HA molecule compared to wild-type HA; and an altered camphecene-binding site. Therefore, despite the relatively rapid development of resistance, camphecene remains promising as a potential antiviral due to the low pathogenicity of resistant viruses that may arise.

Synthesis of Camphecene and Cytisine Conjugates Using Click Chemistry Methodology and Study of Their Antiviral Activity

“…We excluded M2 proton channel due to small size of known inhibitors of it, such as rimantadine, amantadine and deitiforinum . According to, novel camphor‐based antiviral camphecene is antiviral active by binding to active sites of hemagglutinin. The new molecule 13 includes (+)‐camphor fragment so the HA examining seems logical.…”

Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications

“…The most common (+)-camphor-based imine is camphecene 93 ( Figure 23 ), 2-( E )-((1 R ,4 R )-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ylidene-aminoethanol, which was established as an effective inhibitor of influenza virus H1N1 with a selectivity index (SI) value of 500.3 [ 88 ] together with low toxicity. Camphecene remains promising as a potential antiviral due to the low pathogenicity of resistant viruses that may arise [ 92 ].…”

Quaternary Ammonium Salts Based on (-)-Borneol as Effective Inhibitors of Influenza Virus

“…To characterize the details of interaction of compound 10a directly with the hemagglutinin, the docking of the lead-compound, 10a, into the binding site of HA was performed and the calculated docking scores were compared with the values for the well-known HA inhibitor tert-butylhydroquinone, TBHQ, and the new anti-in uenza drug camphecene ( Figure 6). Two binding sites of HA were considered; the rst was located in the binding region for TBHQ [ 20 ] and the second was found near a site of proteolysis, where camphecene binds [ 21 ].…”

“…The functional amino acid sequence was compared in two PDB codes and the area of the TBHQ binding was detected in the protein 3LZG and was used for further docking procedures The CPH-binding site was arranged at the site of proteolysis next to the amino acid valine at position 615 (the numbering corresponds to the 1RU7 [ 25 ] code). Details have been previously described [21].…”