Beta-strand mimicking macrocyclic amino acids: templates for protease inhibitors with antiviral activity.
New amino acids are reported in which component macrocycles are constrained to mimic tripeptides locked in a beta-strand conformation. The novel amino acids involve macrocycles functionalized with both an N- and a C-terminus enabling addition of appendages at either end to modify receptor affinity, selectivity, or membrane permeability. We show that the cycles herein are effective templates within inhibitors of HIV-1 protease. Eleven compounds originating from such bifunctionalized cyclic templates are potent inhibitors of HIV-1 protease (Ki 0.3-50 nM; pH 6.5, I = 0.1 M). Unlike normal peptides comprising amino acids, five of these macrocycle-containing compounds are potent antiviral agents with sub-micromolar potencies (IC(50) 170-900 nM) against HIV-1 replication in human MT2 cells. The most active antiviral agents are the most lipophilic, with calculated values of LogD(6.5) > or = 4. All molecules have a conformationally constrained 17-membered macrocyclic ring that has been shown to structurally mimic a tripeptide segment (Xaa)-(Val/Ile)-(Phe/Tyr) of a peptide substrate in the extended conformation. The presence of two trans amide bonds and a para-substituted aromatic ring prevents intramolecular hydrogen bonds and fixes the macrocycle in the extended conformation. Similarly constrained macrocycles may be useful templates for the creation of inhibitors for the many other proteins and proteases that recognize peptide beta-strands.
Glenn
Matthew P
MP
Centre for Drug Design and Development, Institute for Molecular Bioscience, University of Queensland, Brisbane Qld 4072, Australia.
Pattenden
Leonard K
LK
Reid
Robert C
RC
Tyssen
David P
DP
Tyndall
Joel D A
JD
Birch
Christopher J
CJ
Fairlie
David P
DP
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1; D006801:Humans; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary
D000596:Amino Acids; D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010456:Peptides, Cyclic