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U.S. Department of Health and Human Services

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J Am Chem Soc 2019 Jan 23;141(3):1312-23

Chemical synthesis enables structural reengineering of aglaroxin c leading to inhibition bias for hepatitis C viral infection.

Zhang WH, Liu SF, Maiga RI, Pelletier J, Brown LE, Wang TT, Porco JA


As a unique rocaglate (flavagline) natural product, aglaroxin C displays intriguing biological activity by inhibiting hepatitis C viral entry. To further elucidate structure-activity relationships and diversify the pyrimidinone scaffold, we report a concise synthesis of aglaroxin C utilizing a highly regioselective pyrimidinone condensation. We have prepared more than 40 aglaroxin C analogues utilizing various amidine condensation partners. Through biological evaluation of analogues, we have discovered two lead compounds, CMLD012043 and CMLD012044, which show preferential bias for the inhibition of hepatitis C viral entry vs translation inhibition. Overall, the study demonstrates the power of chemical synthesis to produce natural product variants with both target inhibition bias and improved therapeutic indexes.

Category: Journal Article
DOI: 10.1021/jacs.8b11477
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2018-11-04 Entry Last Modified: 2019-03-03