Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 24, Pages 8396-8404Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.09.003
Keywords
CXCR4 inhibitor; peptide; protein epitope mimetics; drug design
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Novel highly potent CXCR4 inhibitors with good pharmacokinetic properties were designed and optimized starting from the naturally occurring beta-hairpin peptide polyphemusin 11. 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. (c) 2006 Published by Elsevier Ltd.
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