Discovery of novel, highly potent and selective β-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles

Anti-HIV Activity and Resistance Profile of the CXC Chemokine Receptor 4 Antagonist POL3026

“…Previous work selected POL3026 by its plasma stability, high selectivity for CXCR4, and favorable pharmacokinetic properties in dogs (DeMarco et al, 2006). Here, we characterize the mode of action of POL3026 as an anti-HIV agent.…”

“…The synthesis, purification, and chemical characterization of POL3026 ( Fig. 1) were performed as described previously (DeMarco et al, 2006). The chemokine SDF-1␣ (natural ligand of CXCR4) and the natural ligands of CCR5 MIP-1␣, MIP-1␤, and RANTES were purchased from Peprotech (London, UK).…”

New agents in HSC mobilization

“…1). POL6326 is a macrocyclic peptide that has been demonstrated to be efficacious in mice and humans when used as a monotherapy [25][26][27] and has been the subject of several clinical studies (Table 1). POL6326 was found to be well tolerated when given as an intravenous infusion over 2 h, with maximum mobilization observed after approximately 6-8 h [28].…”

17 The protein epitope mimetic approach to protein-protein interaction inhibitors

“…Based on the solution structure of polyphemusin II, several PEM molecules were designed and optimized in biological assays. This led to highly potent and selective CXCR4 antagonist such as POL3026, POL5551 and POL6326 (DeMarco et al 2006;Robinson et al 2008). POL6326 has now successfully moved into a phase II clinical trial for autologous stem cell transplantation in newly diagnosed multiple myeloma patients.…”

“…Upon transplanting the loop from the protein of interest, the cross-strand residue pair directly attached to the D-Pro-L-Pro template then occupay a hydrogenbonding position. In this way, accurate structural mimetics have been produced of CDR loops found in antibodies (Favre et al 1999), of a ß-hairpin loop in Tat bound to HIV-1 TAR-RNA (Athanassiou et al 2004Davidson et al 2009;Lalonde et al 2011;Leeper et al 2005), of protease inhibitors related to the Bowman-Birk family (Descours 2002), and of cationic host-defence peptides related to protegrin-I Shankaramma et al 2002Shankaramma et al , 2003Srinivas et al 2010) and polyphemusin (DeMarco et al 2006). In another example, a 13-residue disulfi de cross-linked loop taken from a phage display peptide that binds a human antibody Fc fragment (discussed previously in this section) (DeLano et al 2000) was transplanted onto a D-Pro-L-Pro template ).…”