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.
MeSH terms
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Animals
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacokinetics
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Anti-HIV Agents / pharmacology*
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Antimicrobial Cationic Peptides / chemistry*
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Calcium / metabolism
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Chemokine CXCL12
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Chemokines, CXC / metabolism
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Chemokines, CXC / pharmacology
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Chemotaxis / drug effects
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Dogs
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Drug Design
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HIV-1 / drug effects*
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HIV-1 / physiology
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Humans
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Leukemia / pathology
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Microsomes / drug effects
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Molecular Mimicry*
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Oligopeptides / chemistry
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Oligopeptides / pharmacokinetics
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Oligopeptides / pharmacology*
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Peptides, Cyclic / chemistry
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Peptides, Cyclic / pharmacokinetics
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Peptides, Cyclic / pharmacology*
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Protein Binding
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Protein Structure, Secondary
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptors, CXCR4 / antagonists & inhibitors*
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Tumor Cells, Cultured
Substances
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Anti-HIV Agents
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Antimicrobial Cationic Peptides
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CXCL12 protein, human
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Chemokine CXCL12
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Chemokines, CXC
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Oligopeptides
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POL2438 peptide
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POL3026 peptide
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Peptides, Cyclic
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Receptors, CXCR4
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polyphemusin II
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Calcium