Journal of Medicinal Chemistry p. 6909 - 6927 (2015)
Update date:2022-08-15
Topics:
Curreli, Francesca
Kwon, Young Do
Zhang, Hongtao
Scacalossi, Daniel
Belov, Dmitry S.
Tikhonov, Artur A.
Andreev, Ivan A.
Altieri, Andrea
Kurkin, Alexander V.
Kwong, Peter D.
Debnath, Asim K.
Earlier we reported the discovery and design of NBD-556 and their analogs which demonstrated their potential as HIV-1 entry inhibitors. However, progress in developing these inhibitors has been stymied by their CD4-agonist properties, an unfavorable trait for use as drug. Here, we demonstrate the successful conversion of a full CD4-agonist (NBD-556) through a partial CD4-agonist (NBD-09027), to a full CD4-antagonist (NBD-11021) by structure-based modification of the critical oxalamide midregion, previously thought to be intolerant of modification. NBD-11021 showed unprecedented neutralization breath for this class of inhibitors, with pan-neutralization against a panel of 56 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates (IC50 as low as 270 nM). The cocrystal structure of NBD-11021 complexed to a monomeric HIV-1 gp120 core revealed its detail binding characteristics. The study is expected to provide a framework for further development of NBD series as HIV-1 entry inhibitors for clinical application against AIDS.
View MoreZhejiang Bolaite Technology Co.,Ltd
Contact:+86-0570-6523168 +86-0570-6523150
Address:No.5 YinKeng Road Kaihua Industrial Park(Chengguan Town) Zhejiang Prov.
Suzhou Tianma Specialty Chemicals Co.,Ltd
Contact:+86-512-68090577
Address:#199, Huayuan Rd, Mudu, Suzhou, Jiangsu, CHINA
Contact:+86 21 5017 5386
Address:No 999,Jiangyue Rd, Minhang Dist ,201114,Shanghai ,China
TIANJIN NORTH JINHENG CHEMICAL PLANT.
Contact:0086-22-59952083
Address:DongShigu Country In JiXian TianJin China
Changzhou BaoKang Pharmaceutical & Chemical Co., Ltd
Contact:(86) 519-88782201 88784080 88785278
Address:Henglin town, changzhou,Jiangsu
Doi:10.1139/v97-172
(1997)Doi:10.1007/BF00773109
(1980)Doi:10.1021/ja952144x
(1996)Doi:10.1515/znb-2001-1002
(2001)Doi:10.1039/b804905j
(2008)Doi:10.1016/j.ica.2020.120190
(2020)