TY - JOUR
T1 - Quinazolinone-based subchemotypes for targeting HIV-1 capsid protein
T2 - design and synthesis
AU - Akther, Thamina
AU - McFadden, William M.
AU - Zhang, Huanchun
AU - Kirby, Karen A.
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
PY - 2024/12
Y1 - 2024/12
N2 - The recent FDA-approval of lenacapavir (LEN, GS-6207) and the subsequent discovery of GSK878 strongly validate HIV-1 capsid protein (CA) as a target for antiviral development. However, multiple single mutations drastically reduced the susceptibility of HIV-1 to both GS-6207 and GSK878, necessitating the design and synthesis of novel sub-chemotypes. With the aid of induced-fit molecular docking, we have designed a few new hybrids combining the quinazolinone scaffold of GSK878 and an N-terminal cap from other CA-targeting chemotypes. We have also worked out a modular synthesis of these novel subtypes. Although these new analogs only weakly inhibited HIV-1 and produced relatively small shifts in the thermal shift assay against pre-assembled CA hexamers, the design and synthesis reported herein inform future design and synthesis of structurally more elaborate analogs for improved potency.
AB - The recent FDA-approval of lenacapavir (LEN, GS-6207) and the subsequent discovery of GSK878 strongly validate HIV-1 capsid protein (CA) as a target for antiviral development. However, multiple single mutations drastically reduced the susceptibility of HIV-1 to both GS-6207 and GSK878, necessitating the design and synthesis of novel sub-chemotypes. With the aid of induced-fit molecular docking, we have designed a few new hybrids combining the quinazolinone scaffold of GSK878 and an N-terminal cap from other CA-targeting chemotypes. We have also worked out a modular synthesis of these novel subtypes. Although these new analogs only weakly inhibited HIV-1 and produced relatively small shifts in the thermal shift assay against pre-assembled CA hexamers, the design and synthesis reported herein inform future design and synthesis of structurally more elaborate analogs for improved potency.
KW - GSK878
KW - HIV-1 capsid
KW - Induced-fit docking
KW - Synthesis
UR - https://www.scopus.com/pages/publications/85204155470
UR - https://www.scopus.com/pages/publications/85204155470#tab=citedBy
U2 - 10.1007/s00044-024-03305-0
DO - 10.1007/s00044-024-03305-0
M3 - Article
C2 - 40182063
AN - SCOPUS:85204155470
SN - 1054-2523
VL - 33
SP - 2431
EP - 2447
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 12
M1 - e0169422
ER -
