Characterization of lassa virus cell entry inhibitors: determination of the active enantiomer by asymmetric synthesis.
The comparative characterization of a series of 4-acyl-1,6-dialkylpiperazin-2-ones as potent cell entry inhibitors of the hemorrhagic fever arenavirus Lassa (LASV) is disclosed. The resolution and examination of the individual enantiomers of the prototypical LASV cell entry inhibitor 3 (16G8) is reported and the more potent (-)-enantiomer was found to be 15-fold more active than the corresponding (+)-enantiomer. The absolute configuration of (-)-3 was established by asymmetric synthesis of the active inhibitor (-)-(S)-3 (lassamycin-1). A limited deletion scan of lassamycin-1 defined key structural features required of the prototypical inhibitors.
Whitby
Landon R
LR
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA.
Lee
Andrew M
AM
Kunz
Stefan
S
Oldstone
Michael B A
MB
Boger
Dale L
DL
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D007836:Lassa virus / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; D001572:Benzofurans; D010879:Piperazines; C544465:lassamycin-1