Zika is an emerging mosquito-borne virus for which there are no
vaccines or specific therapeutics. Zika virus infection during pregnancy has been linked to a range of birth defects including microcephaly.
A panel of small molecules that inhibit Zika virus infection,
including one that stands out as a potent inhibitor of Zika viral entry
into relevant human cell types, was discovered by researchers from the
Perelman School of Medicine at the University of Pennsylvania.
‘Nanchangmycin is a potent inhibitor of Zika virus entry across all cell types tested, including endothelial and placental cells, which are relevant to how Zika may enter the fetus.’
Publishing in Cell Reports
this week, a team led by Sara
Cherry, an associate professor of Microbiology, screened a library
of 2,000 bioactive compounds for their ability to block Zika virus
infection in three distinct cell types using two strains of the virus.
The team used cells lining brain
capillaries called endothelium, and cells from placenta, which represent
Zika's route across the blood-brain barrier and the transmission path
from mother to child, respectively. The third type - a human
osteosarcoma cell line - is a generic model cell. They tested a strain
of Zika virus currently circulating in human populations in the Americas
and another from Africa, which is the original strain identified in
Using a microscopy-based assay, they identified 38 molecules from
the High-throughput Screening Core at Penn, which Cherry directs, that
inhibited Zika virus infection in at least one cell type. Roughly half
of the 2,000 molecules tested include FDA-approved molecules used to
prevent viral replication in infected cells. Co-author David Schultz, the Core's technical director, was instrumental in providing the
infrastructure and expertise for this multi-level screen.
"Overall, the most important finding is that we identified
nanchangmycin as a potent inhibitor of Zika virus entry across all cell
types tested, including endothelial and placental cells, which are
relevant to how Zika may enter the fetus," Cherry said. Nanchangmycin -
an antimicrobial indentified in China as part of a natural medicinal
products survey - was also active against other medically relevant
viruses, including West Nile, dengue, and chikungunya that use a similar
route of entry as Zika.
These viruses enter cells using "clatherin endocytosis." The virus
binds with the host cell's outer membrane via a pocket lined with a
protein called clatherin. This protein-lined sac containing the
sequestered virus pinches off to move deeper into the cytoplasm of the
cell where the virus enters to replicate.
Nanchangmycin is a "stepping stone to a new class of anti-virals,"
Cherry said, because it thwarts this essential mode of entry by viruses
like Zika. Future studies will identify the target of this drug and
current studies are testing the efficacy of nanchangmycin in animal
models of Zika virus infection