title: Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold.
abstract: 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.
authors.affiliation: Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Alterman
authors.forename: M
authors.initials: M
authors.lastname: Björsne
authors.forename: A
authors.initials: A
authors.lastname: Mühlman
authors.forename: B
authors.initials: B
authors.lastname: Classon
authors.forename: I
authors.initials: I
authors.lastname: Kvarnström
authors.forename: H
authors.initials: H
authors.lastname: Danielson
authors.forename: P O
authors.initials: PO
authors.lastname: Markgren
authors.forename: U
authors.initials: U
authors.lastname: Nillroth
authors.forename: T
authors.initials: T
authors.lastname: Unge
authors.forename: A
authors.initials: A
authors.lastname: Hallberg
authors.forename: B
authors.initials: B
authors.lastname: Samuelsson
mesh_terms: 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
chemical_list: D000272:Adipates; D017320:HIV Protease Inhibitors; D010455:Peptides; C114809:mannaric acid; D016333:HIV Protease