TY - JOUR
T1 - Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule
T2 - The HIV-1 CD4:gp120 paradigm
AU - Hurevich, Mattan
AU - Swed, Avi
AU - Joubran, Salim
AU - Cohen, Shira
AU - Freeman, Noam S.
AU - Britan-Rosich, Elena
AU - Briant-Longuet, Laurence
AU - Bardy, Martine
AU - Devaux, Christian
AU - Kotler, Moshe
AU - Hoffman, Amnon
AU - Gilon, Chaim
PY - 2010/8/1
Y1 - 2010/8/1
N2 - Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein-protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules. We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection. The lead compound, CG-1, proved orally available in the rat model.
AB - Rational conversion of noncontinuous active regions of proteins into a small orally bioavailable molecule is crucial for the discovery of new drugs based on inhibition of protein-protein interactions. We developed a method that utilizes backbone cyclization as an intermediate step for conversion of the CD4 noncontinuous active region into small macrocyclic molecules. We demonstrate that this method is feasible by preparing small inhibitor for human immunodeficiency virus infection. The lead compound, CG-1, proved orally available in the rat model.
KW - Backbone cyclization
KW - Drug design
KW - HIV-1
KW - Macrocycles
KW - Proteomics
UR - http://www.scopus.com/inward/record.url?scp=77955422125&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2010.04.053
DO - 10.1016/j.bmc.2010.04.053
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C2 - 20619663
AN - SCOPUS:77955422125
SN - 0968-0896
VL - 18
SP - 5754
EP - 5761
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 15
ER -