Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule: the HIV-1 CD4:gp120 paradigm.
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.
Hurevich
Mattan
M
Institute of Chemistry, The Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram Campus, The Hebrew University, Jerusalem 91904, Israel.
Swed
Avi
A
Joubran
Salim
S
Cohen
Shira
S
Freeman
Noam S
NS
Britan-Rosich
Elena
E
Briant-Longuet
Laurence
L
Bardy
Martine
M
Devaux
Christian
C
Kotler
Moshe
M
Hoffman
Amnon
A
Gilon
Chaim
C
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar
D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D047028:Macrocyclic Compounds; C514793:gp120 protein, Human immunodeficiency virus 1