 |
PDBsum entry 6ogs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Viral protein/inhibitor
|
PDB id
|
|
|
|
6ogs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Single atom changes in newly synthesized HIV protease inhibitors reveal structural basis for extreme affinity, High genetic barrier, And adaptation to the HIV protease plasticity.
|
|
|
Authors
|
|
H.Bulut,
S.I.Hattori,
H.Aoki-Ogata,
H.Hayashi,
D.Das,
M.Aoki,
D.A.Davis,
K.V.Rao,
P.R.Nyalapatla,
A.K.Ghosh,
H.Mitsuya.
|
|
|
Ref.
|
|
Sci Rep, 2020,
10,
10664.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
|
|
|
Abstract
|
|
|
HIV-1 protease inhibitors (PIs), such as darunavir (DRV), are the key component
of antiretroviral therapy. However, HIV-1 often acquires resistance to PIs.
Here, seven novel PIs were synthesized, by introducing single atom changes such
as an exchange of a sulfur to an oxygen, scission of a single bond in
P2'-cyclopropylaminobenzothiazole (or -oxazole), and/or P1-benzene ring with
fluorine scan of mono- or bis-fluorine atoms around DRV's scaffold. X-ray
structural analyses of the PIs complexed with wild-type Protease
(PRWT) and highly-multi-PI-resistance-associated
PRDRVRP51 revealed that the PIs better adapt to
structural plasticity in PR with resistance-associated amino acid substitutions
by formation of optimal sulfur bond and adaptation of cyclopropyl ring in the
S2'-subsite. Furthermore, these PIs displayed increased cell permeability and
extreme anti-HIV-1 potency compared to DRV. Our work provides the basis for
developing novel PIs with high potency against PI-resistant HIV-1 variants with
a high genetic barrier.
|
|
|
|
|
|
|
