Progress Toward Rationally Designed Small-Molecule Peptide and Peptidomimetic CXCR4 Antagonists

Abstract

Over the last five years, X--ray structures of CXC chemokine receptor 4 (CXCR4) in complex with three different ligands (the small--molecule antagonist IT1t, the polypeptide antagonist CVX15, and the viral chemokine antagonist vMIP--II) have been released. In addition to the inherent scientific value of these specific X--ray structures, they (i) provide a reliable structural foundation for studies of the molecular interactions between CXCR4 and its key peptide ligands (CXCL12 and HIV--1 gp120); and (ii) serve as valuable templates for further development of small--molecule CXCR4 antagonists with therapeutic potential. We here review recent computational studies of the molecular interactions between CXCR4 and its peptide ligands -based on the X--ray structures of CXCR4 -and the current status of small--molecule peptide and peptidomimetic CXCR4 antagonists. 2) Isostere: In the context of this review, an isostere is defined as any functional group or moiety that is included in a peptide sequence as a replacement of an amide bond.3) Scaffold: The term scaffold is used for rigid (normally cyclic) structures onto which the functional groups of amino acid side chains can be introduced. 4) Structure--based and ligand--based design:In structure--based design, the 3D structure of the target is known and guides the design of active compounds. When the 3D structure of the target is unknown, indirect information has to be used in order to design/optimize compounds that bind to the target. This information is normally obtained through SAR studies and pharmacophore modeling, and the overall approach is known as ligand--based design. 5) 7TM receptors: As signalling via G proteins is a common feature for seven--

Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity

“…These pairs include CXCR4 M16C, Y21C, and S23C with [P2G]CXCL12 H25C and CXCR4 G19C with [P2G]CXCL12 K27C. We therefore sought to determine whether these proximities were consistent with other complex geometries proposed in the literature so far [6,25,51,52]. Previously published geometries were also incompatible with the offending cross-links, and, in fact, they are incompatible with the majority of cross-linking data generated here, including strong cross-links such as CXCR4 K25C with CXCL12 E15C, CXCR4 Y21C with CXCL12 H17C, and CXCR4 Y7C with CXCL12 H25C (S11 Fig).…”

“…Our final model predicted several salt-bridge type interactions in CRS1 that were not identified by previously published models [25,51] and were also outside of the set of distance restraints used in the simulation. These included two salt bridges: one between CXCR4 E26 and CXCL12 R47 and another between CXCR4 D20 and CXCL12 K56 (Fig 5, S2 Data).…”

“…(TIF) For each model, pairwise residue Cβ-Cβ distances were ranked and receiver operating characteristic curves were generated based on their ability to recognize: (A) the top 10% (14 crosslinks), (B) the top 25% (36), or (C) the top 50% (72) strongest experimentally determined cross-links. Model "Ngo" is our proposed model in this study (S2 Data), and "Tamamis" and "Ziarek" are models published previously [25,51]. The underlying numerical data for each figure panel can be found in S1 Data.…”

Chemokines encoded by herpesviruses

“…Preclinical studies have shown that vCCL2 can control SIV infection in vivo [188], which provides proof of principle for development and application of vCCL2-based anti-HIV peptides. Interestingly, vCCL2-derived N-terminal peptides have been identified that lack CCR5 specificity while retaining CXCR4 specificity [189,190]. Thus, these peptides are candidate-specific inhibitors of X4 strains of HIV [191].…”

Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

“…6 Since the CXCR4/CXCL12 axis also has been shown to have a pathological role in HIV, cancer and rheumatoid arthritis 7 CXCR4 is an attractive drug target, and several small-molecule CXCR4 antagonists have been described in the literature. [7][8][9] Plerixafor, the only small-molecule CXCR4 antagonist that has been approved so far, is used for mobilization of hematopoietic stem cells prior to autologous bone marrow transplantation in patients with Hodgkin disease, non-Hodgkin's lymphoma and multiple myeloma. 10,11 Other small molecule CXCR4 antagonists are undergoing clinical trials; among them is the orally available AMD11070, which is investigated for its efficacy against HIV infection.…”