Analysis of the Mechanism by Which the Small-Molecule CCR5 Antagonists SCH-351125 and SCH-350581 Inhibit Human Immunodeficiency Virus Type 1 Entry

Abstract

Human immunodeficiency virus type 1 (HIV-1

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

“…This resistance pathway often, but not always, results in a virus that is resistant to multiple CCR5 antagonists (22,33,39,53,56). The CCR5 antagonists that have been used clinically all seem to bind to a hydrophobic region in the transmembrane helices of CCR5 and induce conformational alterations in the extracellular domains of the coreceptor that inhibit recognition by gp120 (13,31,32,46,52). These conformational alterations are similar though not identical as judged by the ability of these compounds to affect the binding of various conformation-dependent monoclonal antibodies to CCR5.…”

“…Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sulfated tyrosine residues in the NЈ terminus of CCR5, and (ii) the crown of the V3 loop is thought to engage the extracellular loops (ECLs), particularly ECL2, of CCR5 (10-12, 14, 18, 28). Small-molecule CCR5 antagonists bind to a hydrophobic pocket in the transmembrane helices of CCR5 and exert their effects on HIV by altering the position of the ECLs, making them allosteric inhibitors of HIV infection (13,31,32,46,52). The conformational changes in CCR5 that are induced by CCR5 antagonists vary to some degree with different drugs, as evidenced by differential binding of antibodies and chemokines to various drug-bound forms of CCR5 (47,54).…”

Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636)

“…His 281 in TM7 forms an aromatic π-π stacking interaction with the pyridine ring, and Asp 262 in TM6 is involved in a bidentate interaction with the charged secondary amine in the R 1 side chain of 1. 55,56 Thus, mutations of the aforementioned three residues could destabilize the hydrophobic subpocket that interacts with the naphthyl ring of 1. Furthermore, the observation that Tyr 116 is involved in a direct interaction with Glu 288 (see Supporting Information, Figure S1) implies that the Y116A mutation can affect the overall geometry of the main binding crevice, specifically the orientations of TM3 and TM7.…”

Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants

“…Small-molecule CCR5 inhibitors such as the licensed drug maraviroc (MVC) and the experimental compound vicriviroc (VVC) impair this interaction by a predominantly noncompetitive mechanism. They do so by binding in a hydrophobic cavity located within the transmembrane (TM) helices, thereby stabilizing a CCR5 conformation that HIV-1 recognizes inefficiently (6,7). Viruses resistant to small-molecule CCR5 inhibitors can be generated in vitro and in vivo; the dominant route to resistance involves the acquisition of sequence changes, particularly in V3, that render gp120 capable of recognizing the inhibitor-CCR5 complex while retaining the ability to also interact with the free coreceptor (8)(9)(10).…”