TY - JOUR

T1 - N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry

AU - Kononova, A. A.

AU - Sokolova, A. S.

AU - Cheresiz, S. V.

AU - Yarovaya, O. I.

AU - Nikitina, R. A.

AU - Chepurnov, A. A.

AU - Pokrovsky, A. G.

AU - Salakhutdinov, N. F.

N1 - Publisher Copyright: © 2017 The Royal Society of Chemistry.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

KW - ACID

KW - ANALGESIC ACTIVITY

KW - ANTIVIRAL DRUG DISCOVERY

KW - CELL ENTRY

KW - DISEASE

KW - EBOLA-VIRUS

KW - FILOVIRUS PROTEINS

KW - INFECTION

KW - METHOXY GROUPS

KW - MONOTERPENE MOIETIES

UR - http://www.scopus.com/inward/record.url?scp=85038566254&partnerID=8YFLogxK

U2 - 10.1039/c7md00424a

DO - 10.1039/c7md00424a

M3 - Article

C2 - 30108738

AN - SCOPUS:85038566254

VL - 8

SP - 2233

EP - 2237

JO - MedChemComm

JF - MedChemComm

SN - 2040-2503

IS - 12

ER -