N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry

Abstract

There is currently no approved antiviral therapy for treatment of Marburg virus disease (MVD). Although filovirus infection outbreaks are quite rare, the high mortality rates in such outbreaks make the development of anti-filoviral drugs an important goal of medical chemistry and virology. Here, we performed screening of a large library of natural derivatives for their virus entry inhibition activity using pseudotype systems. The bornyl ester derivatives containing saturated N-heterocycles exhibited the highest antiviral activity. It is supposed that compounds with specific inhibitory activity toward MarV-GP-dependent virus entry will inhibit the rVSIV-ΔG-MarV-GP pseudotype much more efficiently than the control rVSIV-ΔG-G pseudotype. At the same time, the compounds similarly inhibiting both pseudotypes will likely affect rVSIV capsid replication or the cellular mechanisms common to the entry of both viruses. Borneol itself is not active against both pseudotypes and is nontoxic, whereas its derivatives have varying toxicity and antiviral activity. Among low-toxic borneol derivatives, six compounds turned out to be relatively specific inhibitors of MarV-GP-mediated infection (SC > 10). Of them, compound 6 containing a methylpiperidine moiety exhibited the highest virus-specific activity. Notably, the virus-specific activity of this compound is twice as high as that of the reference.

Fig. 1. Both pseudotypes enter via endocytosis and initially share the early endocytic pathway. In early endosomes, the VSIV-G pseudotype merges endosomal and viral membranes and releases its capsid into the cytosol. In contrast, the MarV-GP pseudotype continues its traffic along the endosomal pathway and undergoes proteolytic cleavage by cathepsins in late endosomes. After the endolysosomal fusion, the MarV-GP pseudotype binds to its cognate receptor, NPC1, thus, inducing membrane fusion and releasing the capsid into the cytosol. Specific MarV-GP inhibitors are expected to inhibit the stages of pseudovirus entry, which are not shared with the VSIV-G pseudovirus.