Science - USA (2022-02-25)

830-A 25 FEBRUARY 2022 • VOL 375 ISSUE 6583 science.org SCIENCE

INSIGHTS | PRIZE ESSAY

main, and the carboxyl-terminal β-ladder
( 18 ). The crystal structure of NS1 com-
plexed with 2B7 revealed that 2B7 bound
the β-ladder directly but at an angle so that
2B7 ended up blocking the wing domain as
well ( 17 ). This structure predicted that 2B7
would inhibit the NS1 β-ladder domain to
which it bound while indirectly hindering
the wing domain from interacting with
endothelial cells. We tested this prediction
by producing recombinant NS1 proteins
with mutations in the β-ladder or wing do-
mains and found that these were defective
in mediating pathology. We concluded that
2B7 simultaneously blocked residues in the
wing domain of NS1 critical for cell binding
as well as directly binding to residues in the
β-ladder essential for pathogenesis down-
stream of cell binding ( 17 ).
Continued examination of 2B7 and its
NS1 binding site revealed that this domain
is highly conserved among flaviviruses.
We tested whether 2B7 bound to diverse
flavivirus NS1 proteins and found that
2B7 bound strongly to NS1 proteins from
multiple flaviviruses, including DENV1

to DENV4, ZIKV, and WNV ( 17 ). The pos-

sibility that the strong flavivirus cross-

reactivity of 2B7 would confer cross-

flavivirus protection against NS1 patho-

genesis warranted further study. We con-

ducted in vitro endothelial dysfunction as-

says and in vivo lethal flavivirus challenge

experiments, revealing that 2B7 inhibited

DENV, ZIKV, and WNV NS1 in vitro and

was protective in in vivo lethal challenge

models of both DENV and ZIKV. Years of

research initiated by multiple laborato-

ries culminated in our revealing not only

critical domains for NS1 pathogenesis but

also a highly conserved flavivirus epitope

within the NS1 β-ladder, with the potential

to serve as a molecular road map for the ra-

tional design of NS1-targeted therapeutics.

Therapeutic approaches focused on NS1

are a viable alternative strategy to targeting

the E protein, given the risk of ADE, and

focusing on highly conserved sites within

NS1 can achieve flavivirus cross-protection.

Further, antagonizing multiple domains of

NS1 simultaneously may achieve greater

protective efficacy. Ultimately, our study of

2B7 holds the potential to shift the current

flavivirus vaccine and therapeutic design

paradigm to one that incorporates NS1 and

prompts further examination of simultane-

ous cross-protection against multiple flavi-

virus infections. j

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10.1126/science.abn9651