|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Viral protein
|
|
|
Title:
|
|
Crystal structure of the HIV capsid hexamer bound to the small molecule long-acting inhibitor, gs-6207
|
|
Structure:
|
|
HIV-1 capsid. Chain: a, b, c, d, e, f. Engineered: yes
|
|
Source:
|
|
Human immunodeficiency virus 1. Organism_taxid: 11676. Gene: gag. Expressed in: escherichia coli. Expression_system_taxid: 562
|
|
Resolution:
|
|
|
2.00Å
|
R-factor:
|
0.210
|
R-free:
|
0.251
|
|
|
Authors:
|
|
T.C.Appleby,J.O.Link,S.R.Yant,A.G.Villasenor,J.R.Somoza,E.Y.Hu, S.D.Schroeder,T.Cihlar
|
|
Key ref:
|
|
J.O.Link
et al.
(2020).
Clinical targeting of HIV capsid protein with a long-acting small molecule.
Nature,
584,
614-618.
PubMed id:
DOI:
|
|
|
Date:
|
|
|
22-Nov-19
|
Release date:
|
01-Jul-20
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
DOI no:
|
Nature
584:614-618
(2020)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Clinical targeting of HIV capsid protein with a long-acting small molecule.
|
|
J.O.Link,
M.S.Rhee,
W.C.Tse,
J.Zheng,
J.R.Somoza,
W.Rowe,
R.Begley,
A.Chiu,
A.Mulato,
D.Hansen,
E.Singer,
L.K.Tsai,
R.A.Bam,
C.H.Chou,
E.Canales,
G.Brizgys,
J.R.Zhang,
J.Li,
M.Graupe,
P.Morganelli,
Q.Liu,
Q.Wu,
R.L.Halcomb,
R.D.Saito,
S.D.Schroeder,
S.E.Lazerwith,
S.Bondy,
D.Jin,
M.Hung,
N.Novikov,
X.Liu,
A.G.Villaseñor,
C.E.Cannizzaro,
E.Y.Hu,
R.L.Anderson,
T.C.Appleby,
B.Lu,
J.Mwangi,
A.Liclican,
A.Niedziela-Majka,
G.A.Papalia,
M.H.Wong,
S.A.Leavitt,
Y.Xu,
D.Koditek,
G.J.Stepan,
H.Yu,
N.Pagratis,
S.Clancy,
S.Ahmadyar,
T.Z.Cai,
S.Sellers,
S.A.Wolckenhauer,
J.Ling,
C.Callebaut,
N.Margot,
R.R.Ram,
Y.P.Liu,
R.Hyland,
G.I.Sinclair,
P.J.Ruane,
G.E.Crofoot,
C.K.McDonald,
D.M.Brainard,
L.Lad,
S.Swaminathan,
W.I.Sundquist,
R.Sakowicz,
A.E.Chester,
W.E.Lee,
E.S.Daar,
S.R.Yant,
T.Cihlar.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
Oral antiretroviral agents provide life-saving treatments for millions of people
living with HIV, and can prevent new infections via pre-exposure
prophylaxis1-5. However, some people living with HIV who are heavily
treatment-experienced have limited or no treatment options, owing to multidrug
resistance6. In addition, suboptimal adherence to oral daily regimens
can negatively affect the outcome of treatment-which contributes to virologic
failure, resistance generation and viral transmission-as well as of pre-exposure
prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents
from new antiretroviral classes can provide much-needed treatment options for
people living with HIV who are heavily treatment-experienced, and additionally
can improve adherence10. Here we describe GS-6207, a small molecule
that disrupts the functions of HIV capsid protein and is amenable to long-acting
therapy owing to its high potency, low in vivo systemic clearance and slow
release kinetics from the subcutaneous injection site. Drawing on X-ray
crystallographic information, we designed GS-6207 to bind tightly at a conserved
interface between capsid protein monomers, where it interferes with
capsid-protein-mediated interactions between proteins that are essential for
multiple phases of the viral replication cycle. GS-6207 exhibits antiviral
activity at picomolar concentrations against all subtypes of HIV-1 that we
tested, and shows high synergy and no cross-resistance with approved
antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single
subcutaneous dose of GS-6207 (450 mg) resulted in a mean
log10-transformed reduction of plasma viral load of 2.2 after
9 days, and showed sustained plasma exposure at antivirally active
concentrations for more than 6 months. These results provide clinical
validation for therapies that target the functions of HIV capsid protein, and
demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent
infection with HIV.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
 |
Links
