title: Discovery of novel, highly potent and selective beta-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles.
abstract: Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring beta-hairpin peptide polyphemusin II. The design involved incorporating important residues from polyphemusin II into a macrocyclic template-bound beta-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized in iterative cycles, resulting in the CXCR4 inhibitors POL2438 and POL3026. The inhibitory potencies of these compounds were confirmed in a series of HIV-1 invasion assays in vitro. POL3026 showed excellent plasma stability, high selectivity for CXCR4, favorable pharmacokinetic properties in the dog, and thus has the potential to become a therapeutic compound for application in the treatment of HIV infections (as an entry inhibitor), cancer (for angiogenesis suppression and inhibition of metastasis), inflammation, and in stem cell transplant therapy.
authors.affiliation: Chemistry Department, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: DeMarco
authors.forename: Heiko
authors.initials: H
authors.lastname: Henze
authors.forename: Alexander
authors.initials: A
authors.lastname: Lederer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moehle
authors.forename: Reshmi
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Barbara
authors.initials: B
authors.lastname: Romagnoli
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
authors.forename: Federico
authors.initials: F
authors.lastname: Brianza
authors.forename: Frank O
authors.initials: FO
authors.lastname: Gombert
authors.forename: Sergio
authors.initials: S
authors.lastname: Lociuro
authors.forename: Christian
authors.initials: C
authors.lastname: Ludin
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Vrijbloed
authors.forename: Jürg
authors.initials: J
authors.lastname: Zumbrunn
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Obrecht
authors.forename: Daniel
authors.initials: D
authors.lastname: Obrecht
authors.forename: Vincent
authors.initials: V
authors.lastname: Brondani
authors.forename: François
authors.initials: F
authors.lastname: Hamy
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D008861:Microsomes / Q000187:drug effects; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D019380:Anti-HIV Agents; D023181:Antimicrobial Cationic Peptides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D009842:Oligopeptides; C516699:POL2438 peptide; C516700:POL3026 peptide; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4; C062386:polyphemusin II; D002118:Calcium