Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold.
A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
Alterman
M
M
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
Björsne
M
M
Mühlman
A
A
Classon
B
B
Kvarnström
I
I
Danielson
H
H
Markgren
P O
PO
Nillroth
U
U
Unge
T
T
Hallberg
A
A
Samuelsson
B
B
D000272:Adipates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D016333:HIV Protease / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000272:Adipates; D017320:HIV Protease Inhibitors; D010455:Peptides; C114809:mannaric acid; D016333:HIV Protease