Maraviroc

High-Throughput Screening Initiatives for CCR5 Ligands

High-throughput screening played a crucial role in the initial identification of potential CCR5 ligands nih.govtandfonline.com. Pfizer screened its compound library, which contained approximately 500,000 molecules, using a chemokine radioligand-binding assay nih.govtandfonline.com. This assay utilized HEK-293 cells expressing CCR5 and measured the inhibition of radiolabeled MIP-1β binding nih.govtandfonline.com.

Medicinal Chemistry Efforts and Analog Synthesis

Extensive medicinal chemistry efforts were undertaken in the development of Maraviroc, involving the synthesis of nearly 1,000 analogues nih.gov. This iterative process aimed to optimize the pharmacological and pharmacokinetic properties of the identified chemical series asm.org.

Preclinical Evaluation and Nomination as a Clinical Candidate

Extensive preclinical evaluations were conducted to assess the pharmacological profile and potential of this compound as a clinical candidate. This compound was confirmed as a selective CCR5 antagonist with potent anti-HIV-1 activity and favorable pharmacological properties. asm.orgresearchgate.net

In cell-based assays, this compound was shown to block the binding of viral envelope protein gp120 to CCR5, thereby preventing the membrane fusion necessary for viral entry. asm.orgresearchgate.net It inhibited chemokine binding and CCR5-mediated signaling, as demonstrated in Ca2+ mobilization and γ-S-GTP binding assays. asm.org this compound did not affect CCR5 cell surface levels or associated intracellular signaling, confirming its function as a CCR5 antagonist. asm.orgresearchgate.net

This compound exhibited potent antiviral activity against a broad spectrum of CCR5-tropic HIV-1 viruses. asm.orgresearchgate.net This included 43 primary isolates from various clades and diverse geographic origins, with a geometric mean 90% inhibitory concentration (IC90) of 2.0 nM. asm.orgresearchgate.net The IC90 values ranged from 0.5 nM to 13.4 nM. asm.org this compound also demonstrated activity against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, including those resistant to existing drug classes, with little difference in sensitivity. asm.orgresearchgate.net

Preclinical in vitro studies indicated no detectable cytotoxicity for this compound and confirmed its high selectivity for CCR5 over a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 μM). asm.orgresearchgate.net

Pharmacokinetic studies were conducted in preclinical in vivo models, such as rats and dogs, following single intravenous and oral administrations. asm.org These studies predicted that this compound would have human pharmacokinetics consistent with once- or twice-daily oral administration. asm.orgresearchgate.net Preclinical data also indicated low cerebrospinal fluid exposure in rats, approximately 10% of free plasma concentrations. tga.gov.au this compound was found to be principally metabolized by the cytochrome P450 system, with CYP3A4 identified as the major metabolizing enzyme. tga.gov.au

Based on its potent antiviral activity against CCR5-tropic HIV-1, favorable pharmacological properties, excellent preclinical safety profile, and acceptable pharmacokinetics, this compound was nominated as a clinical candidate in December 2000. nih.gov

Preclinical Antiviral Activity of this compound against Primary CCR5-tropic HIV-1 Isolates asm.org

This compound Activity in CCR5 Binding and Functional Assays asm.org

Preclinical Pharmacokinetic Data (Representative) asm.org

Selective CCR5 Binding and Antagonism

Maraviroc selectively binds to the human chemokine receptor CCR5. drugbank.compmda.go.jpasm.org This binding is characterized as slowly reversible and selective. hivclinic.ca By binding to CCR5, this compound functions as an antagonist, inhibiting the interaction between the HIV-1 envelope glycoprotein gp120 and CCR5. wikipedia.orgdrugbank.compmda.go.jphivclinic.caasm.org This selective binding is crucial as it prevents a necessary step in the entry process for CCR5-tropic HIV-1 strains. pmda.go.jp Studies have confirmed the high affinity and specificity of this compound binding to human CCR5 through radioligand binding experiments. pmda.go.jp

This compound acts as a negative allosteric modulator of the CCR5 receptor. wikipedia.orgnih.govscirp.org Allosteric modulation involves binding to a site on the receptor distinct from the orthosteric binding site where natural ligands or the viral protein would typically bind. nih.govresearchgate.net This allosteric binding leads to changes in the receptor's conformation. patsnap.comresearchgate.netnih.govasm.orgnih.gov Unlike natural β-chemokine CCR5 ligands, which induce signaling and internalization of the receptor, this compound-bound CCR5 does not signal and remains on the cell surface. researchgate.net

Binding of this compound to CCR5 induces conformational changes in the receptor. patsnap.comresearchgate.netnih.govasm.orgnih.gov this compound is thought to bind within a hydrophobic cavity formed by the transmembrane helices of CCR5. researchgate.netasm.orgdovepress.com This interaction, involving amino acids such as Trp86, Glu283, Tyr108, Tyr251, and Ile198, leads to conformational changes, particularly in the extracellular loops of CCR5. researchgate.netnih.govnih.gov These drug-induced changes result in a receptor conformation that is not recognized by the HIV-1 gp120 protein. researchgate.netnih.gov Different CCR5 antagonists can induce distinct conformational changes in the extracellular loops, suggesting drug-specific alterations. asm.org

The conformational changes induced by this compound binding disrupt the interaction between the HIV-1 gp120 protein and CCR5. patsnap.comwikipedia.orgpmda.go.jpresearchgate.netoup.comnih.gov By altering the shape of CCR5, particularly its extracellular loops, this compound prevents the proper association of gp120 with the co-receptor. researchgate.netnih.govnih.gov This disruption is a key step in blocking viral entry. patsnap.com

This compound directly inhibits the binding of HIV-1 gp120 to CCR5. wikipedia.orgpmda.go.jpasm.orgresearchgate.netoup.comnih.gov This inhibition has been demonstrated in cell-based assays where this compound blocked the binding of viral envelope protein gp120 to CCR5-expressing cells. asm.org The ability of this compound to inhibit soluble gp120 binding to CCR5-expressing cells has been characterized, with studies determining the IC50 for this inhibition. asm.org

By inhibiting the binding of gp120 to CCR5, this compound effectively prevents the subsequent steps required for viral entry, including the fusion of the viral membrane with the host cell membrane. asm.orgresearchgate.netoup.comnih.govnih.govpixorize.comjst.go.jp The interaction between gp120 and CCR5, after initial binding to the CD4 receptor, triggers conformational changes in the viral protein gp41, which are necessary for membrane fusion and entry of the viral core into the target cell. pmda.go.jpresearchgate.net this compound blocks this process by interfering with the gp120-CCR5 interaction. pmda.go.jpasm.orgresearchgate.net

Induced Conformational Changes in CCR5

Impact on Chemokine Binding and Signaling

This compound also impacts the binding of natural chemokines to CCR5 and subsequent intracellular signaling. asm.orgresearchgate.netresearchgate.netwikipedia.org CCR5 is a receptor for several endogenous chemokines, including MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5). pmda.go.jpasm.orgnih.gov this compound acts as a selective antagonist of the binding and intracellular signaling mediated by these chemokines. pmda.go.jp

Studies have shown that this compound inhibits the binding of MIP-1α, MIP-1β, and RANTES to CCR5 in radioligand binding competition assays. asm.org This inhibition of chemokine binding also prevents downstream CCR5 signaling events. asm.org For example, this compound has been shown to inhibit MIP-1β-stimulated γ-S-GTP binding, indicating inhibition of chemokine-dependent stimulation of GDP-GTP exchange at the CCR5/G protein complex. asm.org It also inhibits the downstream event of chemokine-induced intracellular calcium redistribution. asm.org Importantly, this compound does not trigger the release of intracellular calcium, indicating a lack of CCR5 agonist activity. asm.org While this compound blocks chemokine binding and signaling, this is not the primary mechanism by which it exerts its antiviral activity. pmda.go.jp The blockade of chemokine binding by this compound can lead to an increase in circulating levels of CCR5 ligands, as receptor-ligand complexes are typically internalized after binding, and this compound prevents this internalization. ashpublications.org

Determinants of HIV-1 Co-receptor Usage (V3 Loop)

The third hypervariable loop (V3 loop) of the HIV-1 gp120 protein is recognized as the principal determinant of viral tropism and co-receptor specificity. asm.orgnih.govtandfonline.comresearchgate.netoup.complos.org This region, typically 35 to 37 amino acids in length, plays a crucial role in binding to either CCR5 or CXCR4 after gp120 has bound to CD4. asm.orgresearchgate.netplos.org

Furthermore, structural disorder within the V3 loop may contribute to the switch in cell tropism. Research indicates that the V3 loop of CXCR4-tropic viruses may have a significantly higher intrinsic disorder tendency compared to CCR5-tropic viruses. plos.org

Specificity of Maraviroc for CCR5-Tropic HIV-1 Variants

This compound is a CCR5 antagonist, a class of antiretroviral drugs that specifically block the CCR5 co-receptor, thereby preventing HIV-1 entry into host cells that utilize CCR5. researchgate.net Due to its mechanism of action, this compound is only effective against HIV-1 variants that exclusively use CCR5 for entry (CCR5-tropic or R5 viruses). researchgate.net

Research has consistently demonstrated the specificity of this compound for CCR5-tropic HIV-1. Studies evaluating the efficacy of this compound have focused on patient populations harboring R5 viruses. The presence of CXCR4-using variants (CXCR4-tropic or X4, and dual/mixed-tropic or D/M viruses) confers resistance to this compound because these viruses can utilize CXCR4 for entry even when CCR5 is blocked. Therefore, determining viral tropism before initiating this compound therapy is crucial for predicting treatment response.

Methodologies for Research-Based Viral Tropism Determination

Accurate determination of HIV-1 tropism is essential in research settings to understand viral pathogenesis, study the evolution of tropism, and evaluate the potential efficacy of co-receptor antagonists like this compound. Several methodologies have been developed for research-based viral tropism determination, broadly categorized into phenotypic and genotypic assays. scielo.br

Research on Predictive Capacity of Tropism Assays for this compound Efficacy

Extensive research has been conducted to evaluate the predictive capacity of both phenotypic and genotypic tropism assays for the efficacy of this compound. These studies are crucial for guiding clinical decision-making and understanding the implications of viral tropism for treatment outcomes.

Studies have consistently shown that a negative test for CXCR4-using virus by phenotypic or sensitive genotypic assays is a strong predictor of virological response to this compound therapy. Conversely, the presence of detectable CXCR4-using virus, even at low levels, is associated with a significantly reduced likelihood of achieving virological suppression on a this compound-containing regimen.

Research comparing different tropism assay methodologies has highlighted the increased sensitivity of deep sequencing for detecting minority X4 variants compared to traditional sequencing. This increased sensitivity has been shown to improve the prediction of this compound treatment outcomes. For instance, studies have demonstrated that detecting minority X4 populations by deep sequencing is associated with a higher risk of this compound failure compared to results from less sensitive genotypic or phenotypic assays.

Data from clinical trials and observational studies have provided valuable insights into the predictive value of tropism testing. For example, analyses of data from the MOTIVATE studies (Phase 3 trials of this compound) demonstrated that baseline tropism determined by the enhanced sensitivity Trofile assay was a strong predictor of virological response. Patients with R5-tropic virus experienced significantly higher rates of virological success compared to those with D/M tropism. Research using deep sequencing in these and other cohorts has further refined the understanding of the impact of low-level X4 variants on this compound outcomes.

While phenotypic assays like Trofile have been considered the gold standard, the increased sensitivity, speed, and decreasing cost of deep sequencing have made genotypic assays, particularly those utilizing advanced sequencing technologies, increasingly important in research and clinical practice for predicting this compound efficacy. Research continues to refine bioinformatic algorithms for interpreting V3 loop sequences from deep sequencing data to optimize the prediction of co-receptor usage and, consequently, the likelihood of response to CCR5 antagonists.

Table 1: Comparison of Research-Based Viral Tropism Determination Methodologies

Table 2: Examples of Research Findings on Predictive Capacity of Tropism Assays

Emergence of CXCR4-Using Viruses

One significant mechanism of Maraviroc resistance is the emergence of viruses that utilize the CXCR4 coreceptor for entry, either exclusively (X4-tropic) or in addition to CCR5 (dual/mixed-tropic). asm.orgoup.comscientificarchives.com This shift in coreceptor usage renders the virus insensitive to this compound, which specifically targets CCR5. asm.orgoup.com

Mutations Allowing Use of this compound-Bound CCR5

Another mechanism of this compound resistance involves the development of mutations in the viral Env protein, primarily in gp120, that enable the virus to utilize CCR5 even when it is bound by this compound. asm.orgoup.comscientificarchives.com This is known as non-competitive resistance and is characterized by a reduction in the maximal percentage of viral inhibition by this compound. dovepress.comoup.comresearchgate.netresearchgate.netasm.orgasm.org

In Vitro Selection of this compound-Resistant Variants

In vitro studies have been instrumental in understanding how HIV-1 develops resistance to this compound. These experiments often involve exposing viral isolates to increasing concentrations of the drug over time.

Serial passage experiments, where HIV-1 is cultured in the presence of escalating concentrations of this compound, have demonstrated the potential for resistance to emerge tga.gov.auasm.org. While some laboratory-adapted and clinical isolates failed to select for this compound resistance under these conditions, high-level resistance was successfully selected from some primary isolates passaged in peripheral blood lymphocytes (PBLs) asm.orgnih.gov.

For instance, high-level resistance was selected from three out of six primary isolates in one study asm.orgnih.gov. Interestingly, one strain, SF162, acquired resistance in both treated and control cultures, with resistant variants becoming CXCR4-using asm.orgnih.gov. In contrast, this compound-resistant virus derived from isolates like CC1/85 and RU570 remained CCR5-tropic, retaining susceptibility to other CCR5 antagonists like SCH-C and resistance to CXCR4 antagonists like AMD3100 asm.orgnih.gov. These resistant variants showed an inability to replicate in CCR5 Δ32/Δ32 PBLs, further confirming their CCR5 tropism asm.orgnih.gov.

Phenotypic resistance to this compound in R5 viruses is often characterized by a reduced maximal percentage inhibition (MPI) in dose-response curves, rather than a significant shift in the half-maximal inhibitory concentration (IC50) dovepress.comnatap.orgnatap.orgplos.org. This indicates that resistant viral strains can utilize the CCR5 co-receptor even when this compound is bound dovepress.comnatap.orgasm.orgplos.org.

In phenotypic susceptibility assays, a reduced MPI suggests that the virus has acquired the ability to utilize the this compound-bound receptor for entry dovepress.comasm.orgnih.gov. Most resistant viruses typically exhibit an MPI between 80% and 95% dovepress.com. Studies analyzing viruses from patients who experienced virologic failure while on this compound have validated the use of reduced MPI as a phenotypic marker of resistance in vivo natap.org. For example, in the MOTIVATE trials, plateaus in MPI below 95% were identified in some patients failing this compound therapy with R5 virus natap.orgnatap.orgplos.org. Clonal analyses further confirmed that Env clones from these failure time points displayed reduced MPI plos.org.

Cross-Resistance Patterns with Other CCR5 Antagonists

Resistance to one CCR5 antagonist does not always result in broad cross-resistance to other agents in the same class asm.orgresearchgate.netnih.gov. While resistance to some CCR5 antagonists can lead to broad cross-resistance, this compound-resistant viruses have been observed to have narrow cross-resistance patterns asm.orgresearchgate.net.

Studies analyzing viruses from patients failing this compound-containing regimens have shown that while high-level resistance to this compound can develop, these viruses may remain sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc asm.orgresearchgate.netnih.gov. Some this compound-resistant variants have shown partial cross-resistance to compounds like TAK779 but remained sensitive to others researchgate.net. This suggests that the specific mechanisms of resistance can influence the degree of cross-resistance to different CCR5 antagonists asm.org.

Genetic and Structural Basis of this compound Resistance

The development of this compound resistance in R5 viruses is primarily associated with genetic changes in the viral envelope glycoprotein gp120, particularly in the V3 loop region oup.comasm.orgnatap.orgtga.gov.aunatap.orgplos.orgresearchgate.net. These mutations enable the virus to interact with and utilize the CCR5 co-receptor even when this compound is bound dovepress.comoup.comasm.org.

Mutations associated with this compound resistance are frequently found in the V3 loop of gp120 natap.orgtga.gov.auasm.orgnatap.orgplos.orgasm.orgresearchgate.net. However, there is a notable lack of a single, predictable set of "signature" mutations that consistently confer resistance across different patients or isolates asm.orgnatap.orgplos.org. The specific amino acid changes can differ between patients, reflecting the heterogeneity of the gp160 sequence natap.org. While V3 loop mutations are key determinants natap.orgasm.orgnih.govplos.orgasm.org, mutations outside the V3 loop, in other regions of gp120 or even in gp41, can also contribute to resistance asm.orgresearchgate.net.

Structural studies and modeling suggest that this compound binds deep within a hydrophobic pocket in the transmembrane region of CCR5, inducing conformational changes in the extracellular loops (ECLs) dovepress.comresearchgate.netrcsb.orgnih.gov. Resistance mutations in gp120, particularly in the V3 loop, are thought to alter the interaction between gp120 and the drug-bound CCR5 dovepress.comoup.comasm.orgnih.govplos.org. These mutations may lead to increased affinity of gp120 for the CCR5-maraviroc complex, allowing entry despite the conformational changes induced by the drug dovepress.com. Some studies indicate that resistant viruses may show altered reliance on different domains of CCR5, such as increased dependence on the N-terminal domain compared to the ECLs, although this compound-resistant viruses with narrow cross-resistance may still depend on drug-modified ECLs asm.orgasm.org. Molecular dynamics simulations of the gp120 V3 loop with resistance mutations have shown altered V3 loop structure and dynamics, which could facilitate interaction with drug-bound CCR5 plos.org.

The complex and variable nature of the genetic changes associated with this compound resistance presents a challenge for the development of simple genotypic resistance algorithms natap.orgplos.org.

Table 1: Selected Mutations Associated with this compound Resistance

Table 2: Phenotypic Characteristics of this compound Resistance

Table 3: Cross-Resistance of this compound-Resistant Viruses

Potency Against Diverse CCR5-Tropic HIV-1 Isolates (various clades and geographic origins)

Maraviroc has demonstrated potent in vitro antiviral activity against a broad spectrum of CCR5-tropic HIV-1 viruses. Studies involving 43 primary isolates from various clades and diverse geographic origins have shown a geometric mean 90% inhibitory concentration (IC90) of approximately 2.0 nM. The in vitro IC50 (50% inhibitory concentration) for this compound against the replication of HIV-1 group M isolates (subtypes A to J and circulating recombinant form AE) and group O isolates has been reported to range from 0.1 to 4.5 nM (0.05 to 2.3 nanogram/mL) in cell culture. This indicates consistent potency across different major subtypes and geographic sources of CCR5-tropic HIV-1. No single exclusively CCR5-tropic subtype of HIV-1 appeared to have significantly lower susceptibility to this compound than others, although one hybrid subtype (CRF_01(AE)) showed markedly greater susceptibility.

Activity Against HIV-1 Strains Resistant to Other Antiretroviral Classes

A significant finding from in vitro research is this compound's activity against HIV-1 strains that have developed resistance to other classes of antiretroviral agents. HIV-1 clinical isolates resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and enfuvirtide have all shown susceptibility to this compound in cell culture. This lack of cross-resistance with existing agents that target intracellular steps is a key advantage of entry inhibitors like this compound. Studies using clinically derived HIV-1 envelope pseudoviruses, including those from viruses resistant to existing drug classes, also confirmed this compound's activity.

Synergistic Antiviral Effects with Other Antiretroviral Agents in Cell Culture

The combination of this compound with other antiretroviral agents in cell culture has been investigated to understand potential synergistic or additive antiviral effects. Generally, additive or slightly synergistic interactions have been observed when this compound is tested in combination with licensed antiretroviral agents from different classes. This supports the use of this compound in multi-drug regimens for HIV-1 infection.

CCR5 Receptor Structural Characterization and Binding Pocket Analysis

The CCR5 receptor, like other GPCRs, is characterized by a structure comprising seven transmembrane (7TM) α-helices connected by intracellular and extracellular loops. ulb.ac.beacs.orgwikipedia.org The first high-resolution crystal structure of human CCR5 bound to Maraviroc (PDB ID: 4MBS) was reported in 2013, providing crucial insights into the receptor's architecture and ligand binding. scirp.org This structure revealed a ligand binding site located within the 7TM bundle. acs.orgnih.gov

The ligand binding pocket of CCR5 is described as a cavity within the transmembrane domain. wikipedia.orgnih.gov This pocket is notably hydrophobic and lined with multiple aromatic residues. wikipedia.org Compared to other class A GPCRs, the 7TM ligand binding pockets of chemokine receptors like CCR5 are less buried and more solvent accessible. acs.org The extracellular loop 2 (ECL2) covers the pocket to a lesser extent than in most other GPCRs, which is thought to be related to chemokine receptors binding larger chemokine ligands. acs.org

Site-directed mutagenesis and biochemical studies have indicated that small molecule CCR5 inhibitors, including this compound, bind to a hydrophobic cavity within the transmembrane domain. nih.gov This location is distinct from the proposed major binding sites for endogenous chemokines and the viral glycoprotein gp120, which are located at the receptor surface, particularly involving the N-terminus and ECL2. nih.govnih.gov

This compound Binding Site and Specificity Analysis

The crystal structure of the CCR5-Maraviroc complex revealed that this compound is buried in a cavity within the 7TM domain. nih.gov This binding site is distinct from the primary recognition sites for chemokines and gp120. nih.gov this compound is predicted to insert deeply into the CCR5 transmembrane cavity, potentially occupying different binding sites. nih.gov This location suggests that this compound inhibits chemokine function by blocking receptor activation through interactions with a site that potentially overlaps with the chemokine activation site (Site 2), located within the 7TM domain and interacting with the flexible N-terminus of the chemokine. nih.govresearchgate.net

This compound's binding to CCR5 is characterized by its specificity. It functions as an antagonist of CCR5, which is the main co-receptor for R5-tropic HIV-1 strains. nih.govnih.gov The binding site for this compound has been shown to be distinct from that of other CCR5 antagonists like TAK-779, despite some overlap in key residues involved in binding. natap.org Differences in the specific interactions within the binding site can lead to variations in the conformational changes induced and the resulting resistance profiles against different antagonists. natap.org

Conformational Dynamics and Allosteric Shifts Induced by this compound Binding

This compound is characterized as an inverse agonist of CCR5, suggesting that its binding stabilizes the receptor in an inactive conformation. nih.gov This is supported by the conformation of conserved GPCR residues, such as Trp248 and Tyr244, which are involved in transmitting ligand-induced conformational changes. nih.gov In the CCR5-Maraviroc structure, these residues adopt conformations similar to those observed in other inactive GPCR structures. nih.gov

This compound binding to CCR5 provokes an allosteric conformational change that inhibits viral engagement with the co-receptor and prevents entry. nih.gov This allosteric mechanism involves this compound binding to a site distinct from the orthosteric site where chemokines and gp120 bind, yet influencing the conformation of these binding sites. nih.govnih.govmdpi.comasm.org The binding of small molecules like this compound is associated with compound-specific conformational changes in the binding site. natap.org These changes are speculated to translate to compound-specific alterations in the extracellular loops, which in turn modulate the binding site for HIV gp120, preventing viral docking. natap.org Studies have shown that this compound induces conformational changes in the CCR5 receptor to block HIV interaction while still allowing native chemokine internalization of the receptor. mdpi.com

Specific residues are involved in the binding and the induced conformational changes. Key residues for the initial binding of both this compound and another CCR5 inhibitor, RO1752, include W86 and I198. natap.org The residue F85 is involved in the conformational change to the final stable state for both compounds. natap.org However, the conformational change induced by this compound is differentiated by the contribution of Y108 and Y251 to its binding. natap.org Mutation of residues Y108 on helix III and Y251 on helix VI to alanine eliminated the time-dependent binding for this compound, but not for RO1752, indicating distinct dynamics in their binding and induced conformational changes. natap.org

Development of Allosteric Models for CCR5 Antagonism

The observation that this compound binds to a site distinct from the chemokine/gp120 binding site and induces conformational changes has led to the development of allosteric models for CCR5 antagonism. nih.govnih.govasm.org These models propose that this compound binding to a transmembrane cavity allosterically prevents the binding of its natural ligands and gp120 by stabilizing an inactive receptor conformation. nih.govnih.gov

Studies combining site-directed mutagenesis and molecular modeling have supported the view that small molecule CCR5 inhibitors bind to a hydrophobic cavity within the transmembrane domain, acting allosterically. nih.gov An allosteric model suggests that this compound enhances the dissociation of preformed ligand-CCR5 complexes, implying that the transmembrane cavity remains accessible even when other ligands are bound. nih.gov

Allosteric antagonism provides a mechanism where the modulator binds to a site topologically distinct from the orthosteric site but still affects receptor function. nih.govfrontiersin.org In the case of CCR5, this compound's allosteric binding stabilizes a receptor conformation that is not recognized by HIV-1, thereby preventing entry. natap.org This is in contrast to competitive inhibition, where the inhibitor directly competes with the natural ligand for the same binding site.

Application of Molecular Docking and Molecular Dynamics Simulations

Computational techniques such as molecular docking and molecular dynamics (MD) simulations have been extensively applied to study the interaction of this compound with CCR5 and to understand the structural basis of its activity. scirp.orgnih.govmdpi.comzenodo.orgtandfonline.com

Molecular docking is used to predict the binding pose and affinity of this compound within the CCR5 binding pocket. scirp.orgnih.govzenodo.org Studies using docking have predicted that this compound inserts deeply into the transmembrane cavity and can occupy multiple binding sites. nih.gov Docking calculations have also been used in virtual screening approaches to identify potential novel CCR5 inhibitors and compare their predicted binding affinities to that of this compound. nih.govmdpi.comzenodo.org For example, some compounds have shown stronger predicted binding affinities than this compound in docking studies, forming favorable interactions with key CCR5 residues like TYR108, GLU283, and PHE109. zenodo.org

Molecular dynamics simulations provide insights into the dynamic behavior of the CCR5-Maraviroc complex, allowing researchers to study the stability of the binding interaction and the conformational changes induced by this compound binding over time. scirp.orgnih.govmdpi.comtandfonline.com MD simulations can predict atomic motions and validate docking results. scirp.org They are used to assess the binding stability of ligands and gain insights into their binding modes. scirp.org MD simulations have been employed to refine CCR5 models, particularly focusing on the flexible extracellular loops and N-terminal segment, and to produce flexible receptor templates for docking studies. plos.org Furthermore, MD simulations, combined with techniques like principal component analysis (PCA) and free energy landscape (FEL) analysis, are used to investigate the conformational dynamics and allosteric mechanisms of CCR5 antagonists. tandfonline.com

Quantitative Structure-Activity Relationship (QSAR) Studies for CCR5 Antagonists

Quantitative Structure-Activity Relationship (QSAR) studies aim to establish a relationship between the chemical structure of a series of compounds and their biological activity, allowing for the prediction of the activity of new compounds and the design of novel inhibitors with improved properties. tandfonline.comrjptonline.orgeurekaselect.comacs.org QSAR studies have been performed on various series of compounds as CCR5 antagonists, including piperidine and piperazine derivatives. tandfonline.comrjptonline.orgeurekaselect.com

These studies utilize various molecular descriptors (structural, spatial, electronic, physicochemical, and topological parameters) and statistical methods (such as multiple linear regression, partial least squares, and artificial neural networks) to build predictive models. tandfonline.comrjptonline.org QSAR models for CCR5 antagonists have revealed that factors such as steric factors and lipophilicities of substituents play a significant role in determining the antagonistic activity. eurekaselect.com The size and shape of substituents are emphasized as important for effective antagonist-CCR5 binding chemistry. eurekaselect.com

Modulation of T-Cell Homeostasis and Function in Vitro

In vitro studies have investigated the direct effects of maraviroc on human T lymphocytes, providing insights into how CCR5 blockade influences T-cell behavior. oup.comoup.comresearchgate.net

Influence on Host Immune Response Beyond Antiviral Activity

The CCR5 antagonism by this compound extends its influence to the host immune response beyond merely blocking viral entry. oup.comashpublications.orgfrontiersin.orgplos.orgnih.govfda.gov

Interaction with Other Chemokine Receptors and Signaling Pathways

Chemokine receptors are a large family of G protein-coupled receptors (GPCRs) involved in various cellular processes, including immune cell trafficking, inflammation, and cell proliferation. While this compound is designed to specifically target CCR5, understanding its potential interactions with other receptors and downstream signaling cascades is crucial for a comprehensive view of its cellular effects.

Impact on Cell Cycle Regulation in Specific Cell Types

Beyond its role in immune cell function and viral entry, CCR5 signaling has been implicated in regulating cell cycle progression in certain cell types, particularly in the context of cancer. Antagonizing CCR5 with this compound has shown effects on cell proliferation and cell cycle distribution in various cancer cell lines.

Studies on colorectal cancer cells (SW480 and SW620) have indicated that this compound treatment can significantly reduce proliferation and induce an arrest in the G1 phase of the cell cycle alzdiscovery.org. In these cells, this compound also promoted apoptosis alzdiscovery.org.

In gastric cancer cell lines (MKN45, MKN74, and KATOIII), exposure to this compound effectively inhibited cell proliferation nih.gov. Furthermore, in a mouse model of gastric cancer, CCR5 antagonism modulated the expression of genes known for their role in cancer growth, including those related to the cell cycle alzdiscovery.orgnih.gov.

Research in classical Hodgkin lymphoma (cHL) cells has shown that this compound treatment can slightly slow cell growth and slightly increase the percentage of cells in the G1 phase of the cell cycle researchgate.net. While it influenced the cell cycle distribution, in this specific context, this compound treatment did not induce apoptosis or necrosis as measured by certain markers researchgate.net.

Studies investigating the effects of CCR5 blockade by this compound on cell cycle-related signaling cascades in colorectal cancer cells (SW620) have revealed alterations in the expression of numerous genes involved in cell cycle regulation, including cyclins and cyclin-dependent kinases (CDKs) aacrjournals.orgresearchgate.net. This suggests that CCR5 antagonism can interfere with the molecular machinery controlling cell cycle progression researchgate.net.

The impact of this compound on cell cycle regulation appears to be cell type-specific and context-dependent, with notable effects observed in various cancer models, contributing to reduced proliferation and, in some cases, increased apoptosis.

Here is a summary of research findings on this compound's impact on cell cycle regulation in specific cell types:

CCR5 in Cancer Progression and Therapy Research

CCR5 is expressed in various cancers, and its expression level has been suggested as a negative prognostic marker in some malignancies. nih.govresearchgate.net The interaction between cancer cells and their microenvironment, often mediated by chemokine axes like CCR5/CCL5, is critical for tumor progression, including invasion and metastasis. researchgate.net Maraviroc, as a CCR5 antagonist, has been investigated for its potential to interfere with these processes. nih.govresearchgate.net

CCR5 in Inflammatory Diseases Research

CCR5 plays a significant role in inflammatory responses by directing immune cell migration to sites of inflammation. frontiersin.orgtandfonline.com Dysregulation of this process is implicated in various inflammatory diseases. frontiersin.orgtandfonline.com this compound's ability to block CCR5 has led to investigations into its potential to attenuate inflammation in different disease contexts. frontiersin.orgtandfonline.com

Potential in Other Immunological Conditions

Beyond atherosclerosis, the role of CCR5 in immune cell trafficking and inflammation has led to investigations into the potential of CCR5 antagonism in various other immunological and inflammatory conditions. frontiersin.orgtandfonline.comresearchgate.net CCR5 is expressed on key immune cells, including T cells, macrophages, and dendritic cells, and its activation mediates immune responses by binding chemokines like CCL3, CCL4, and CCL5. researchgate.net In chronic inflammatory diseases, affected sites often show increased inflammatory cell infiltrates expressing CCR5 and high levels of its ligands. tandfonline.comnih.gov

The therapeutic potential of targeting CCR5 in inflammatory diseases stems from the observation that blocking CCR5 is likely to specifically affect infiltrating cells at inflammatory sites, potentially leading to reduced local inflammation with minimal systemic immunosuppression. tandfonline.com

Research has explored CCR5 antagonism in conditions such as:

Inflammatory Bowel Disease (IBD): CCR5 is involved in the pathogenesis of IBD and is highly expressed in the colonic mucosa of patients with the condition. archivesofmedicalscience.com Studies using CCR5 antagonist peptides in rat models of colitis have shown inhibitory effects on inflammatory cell infiltration. archivesofmedicalscience.com

Rheumatoid Arthritis (RA): CCR5 is abundantly expressed in the synovium and inflammatory infiltrates in RA. nih.gov While initial clinical trials with CCR5 antagonists, including this compound, in RA patients showed no significant clinical efficacy, the complex nature of RA and the chemokine system warrant further investigation into patient selection and dosing strategies. nih.gov

Multiple Sclerosis (MS): CCR5 is expressed on immune cells within inflammatory lesions in MS and may contribute to their recruitment and activation in the inflamed tissue. frontiersin.org Evidence suggests that while the CCR5Δ32 allele (associated with non-functional CCR5) is not linked to MS risk, the disease may be less severe in carriers, implying that CCR5 antagonists might reduce disease activity. frontiersin.org Studies in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, have shown that CCR5 knockout or antagonism can reduce infiltrating immune cells in the central nervous system (CNS). mdpi.com

Graft-versus-Host Disease (GvHD): The CCR5 receptor appears to play a central role in modulating immune cell trafficking to sites of inflammation, which is crucial in the development of acute GvHD. vax-before-travel.com Clinical studies support the concept that blocking CCR5 can reduce the clinical impact of acute GvHD without significantly affecting bone marrow stem cell engraftment. vax-before-travel.com this compound treatment has been reported to increase CCR5 expression on T cells and reduce T cell activation in peripheral blood, suggesting a potential protective effect against GvHD through modulation of allo-reactive donor T cell responses. frontiersin.org

Sarcoidosis: CCR5 is involved in the TH1 signaling cascade implicated in sarcoidosis. jiaci.org A case report described an HIV-infected patient with pulmonary sarcoidosis who showed both immune restoration and relief of respiratory symptoms following intensification of antiretroviral therapy with this compound. jiaci.org This observation suggests that this compound, as a selective CCR5 inhibitor, warrants further evaluation in sarcoidosis, potentially in non-HIV-infected patients as well. jiaci.org

Neuroinflammatory Diseases: Chemokine receptors, including CCR5, are implicated in various CNS inflammatory diseases and play roles in the recruitment and positioning of immune cells within tissues. researchgate.net this compound has been hypothesized to offer neuroprotective benefits in conditions where CCR5 promotes deleterious neuroinflammation, particularly those involving CD8+ T cells. researchgate.net This includes conditions like HIV-associated neurocognitive disorders. researchgate.net

The involvement of CCR5 in a broad array of chronic inflammatory diseases positions CCR5 antagonism as a potential therapeutic strategy. frontiersin.org While this compound is the only CCR5 antagonist currently approved for clinical use (in HIV), research continues to explore its potential and the potential of other CCR5-targeting approaches in various inflammatory and immunological conditions. frontiersin.orgresearchgate.net

Table of CCR5 Antagonism Research in Other Immunological Conditions:

Development of Novel Maraviroc-Related Analogues with Improved Pharmacological Profiles

Research is ongoing to design and synthesize novel compounds structurally related to this compound with the aim of achieving improved pharmacological profiles. This includes efforts to enhance potency, improve pharmacokinetic properties, and potentially overcome existing limitations such as susceptibility to resistance or drug interactions. Computational studies, including molecular docking and dynamics simulations, are being employed to guide the design of these new analogues by predicting their binding interactions with the CCR5 receptor and evaluating their stability. researchgate.netnih.govtandfonline.com For instance, in silico investigations have explored novel this compound analogues for potential dual inhibition of CCR5 and other targets like SARS-CoV-2 Mpro, suggesting structures that could be synthesized and evaluated in vitro and in vivo. researchgate.nettandfonline.com

Deeper Elucidation of Resistance Mechanisms and Predictive Markers

Understanding the mechanisms by which HIV-1 develops resistance to this compound is crucial for its continued effectiveness and the development of next-generation CCR5 antagonists. Research indicates that resistance can arise through mutations in the V3 loop of the viral gp120 protein, allowing the virus to utilize this compound-bound CCR5 coreceptors. oup.comnih.gov Another mechanism involves a shift in viral tropism from CCR5 to CXCR4 usage. oup.comnih.gov Future research aims to more deeply elucidate these resistance pathways and identify predictive markers that can forecast treatment failure. Studies have utilized phenotypic assays, such as the PhenoSense Entry assay, to identify reduced maximal percentage inhibition (MPI) as a marker of this compound resistance in patient samples, correlating this with V3 loop mutations. natap.org However, the diverse patterns of amino acid changes observed suggest the need for further research to establish canonical mutations and develop reliable genotypic algorithms for predicting resistance. nih.gov Research is also exploring the predictive value of immunological markers, such as the CD4/CD8 ratio, in identifying patients at higher risk of disease progression despite viral suppression, which could potentially inform treatment strategies including the use of this compound. clinicalstudydatarequest.com

Advanced Computational and Structural Studies for Rational Drug Design

Computational and structural studies play a vital role in the rational design of improved CCR5 inhibitors. The availability of the crystal structure of the CCR5-Maraviroc complex has significantly advanced the ability to investigate protein-ligand interactions at a molecular level. scirp.org Techniques such as molecular dynamics (MD) simulations, accelerated MD simulations, and free energy calculations are employed to understand the detailed interaction mechanisms between this compound and CCR5. nih.gov These studies provide insights into the flexibility of different parts of the this compound molecule within the binding pocket and the energetic landscape of its dissociation. nih.gov This information is invaluable for designing more potent and effective CCR5 antagonists with desired binding characteristics and improved pharmacological profiles. nih.govscirp.org Structure-based pharmacophore modeling, using this compound as a template, is also utilized for virtual screening of large databases to identify novel CCR5 inhibitors with favorable properties. scirp.org