Novel Compounds Containing Multiple Guanide Groups That Bind the HIV Coreceptor CXCR4

Abstract

The G-protein-coupled receptor CXCR4 acts as a coreceptor for human immunodeficiency virus type 1 (HIV-1) infection, as well as being involved in signaling cell migration and proliferation. Compounds that block CXCR4 interactions have potential uses as HIV entry inhibitors to complement drugs such as maraviroc that block the alternate coreceptor CCR5 or in cancer therapy. The peptide T140, which contains five arginine residues, is the most potent antagonist of CXCR4 developed to date. In a search for nonpeptide CXCR4 ligands that could inhibit HIV entry, three series of compounds were synthesized from 12 linear and branched polyamines with 2, 3, 4, 6, or 8 amino groups, which were substituted to produce the corresponding guanidines, biguanides, or phenylguanides. The resulting compounds were tested for their ability to compete with T140 for binding to the human CXCR4 receptor expressed on mammalian cells. The most effective compounds bound CXCR4 with a 50% inhibitory concentration of 200 nM, and all of the compounds had very low cytotoxicity. Two series of compounds were then tested for their ability to inhibit the infection of TZM-bl cells with X4 and R5 strains of HIV-1. Spermine phenylguanide and spermidine phenylguanide inhibited infection by X4 strains, but not by R5 strains, at low micromolar concentrations. These results support further investigation and development of these compounds as HIV entry inhibitors.

Antibacterial Activity of THAM Trisphenylguanide against Methicillin-Resistant Staphylococcus aureus

“…The TOAM guanide derivatives were synthesized as described previously for the corresponding THAM compounds [4].…”

“…Some of these compounds were previously found to be effective as antagonists of CXCR4 and inhibited HIV infection by X4 strains [4], [5] and the formation of metastatic tumors [6]. The biguanide series of compounds are chemically related to some commercially important biocidal agents found in common household items such as disinfectants, mouthwashes, contact lens solutions, and cosmetics.…”

Small Molecule Inhibitors of CXCR4

“…Small molecules containing multiple guanide or biguanide groups are capable of inhibiting HIV-1 binding to CXCR4 100. In particular, an oligomer based on a biguanide moiety, NB325, showed wide antiviral activity in several in vitro assays.…”

“…However, since such preparation consists of a variable mixture of compounds containing from 4 to 10 biguanide groups, endowed with intractable activities, its development will be challenging. This study therefore focused on the design and development of a series of single small molecules containing multiple guanide or biguanide groups ( Table 2, Figure 20 ) 100. These compounds include some features of the polyethylene-hexamethylene biguanide NB325, as well as the peptide T140 that has five guanide groups on the side chains of arginine residues.…”

Mapping the Ligand-Binding Site on a G Protein-Coupled Receptor (GPCR) Using Genetically Encoded Photocrosslinkers

“…This T140 derivative has been reported to crosslink to CXCR4 and serves as a positive control (18). We also demonstrated that FL-T140-BzF crosslinks specifically to CXCR4 in cell culture.…”