Anti-Human Immunodeficiency Virus Interactions of SCH-C (SCH 351125), a CCR5 Antagonist, with Other Antiretroviral Agents In Vitro

Abstract

SCH-C (SCH 351125) is a small-molecule antagonist of the human immunodeficiency virus type 1(HIV-1) coreceptor CCR5. It has in vitro activity against R5 viruses with 50% inhibitory concentrations ranging from 1.0 to 30.9 nM. We have studied anti-HIV-1 interactions of SCH-C with other antiretroviral agents in vitro. Synergistic interactions were seen with nucleoside reverse transcriptase inhibitors (zidovudine and lamivudine), nonnucleoside reverse transcriptase inhibitors (efavirenz), and protease inhibitors (indinavir) at all inhibitory concentrations evaluated. We have also studied antiviral interactions between the HIV-1 fusion inhibitor T-20 and SCH-C against a panel of R5 HIV-1 isolates. We found synergistic interactions against all the viruses tested, some of which harbored resistance mutations to reverse transcriptase and protease inhibitors. Anti-HIV-1 synergy was also observed between SCH-C and another R5 virus inhibitor, aminooxypentane-RANTES. These findings suggest that SCH-C may be a useful anti-HIV drug in combination regimens and that a combination of chemokine coreceptor/fusion inhibitors may be useful in the treatment of multidrug-resistant viruses.

Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

“…In previous drug combination studies employing molecules that disrupt gp120 -coreceptor interactions and C-peptide T20, synergy was not consistently observed (31,(43)(44)(45)(46)(47). Our findings pointed to several possible explanations for this variability.…”

“…As differences in gp120-chemokine receptor affinity could alter the coreceptor stoichiometry required for entry, we hypothesize that gp120 sequence variation among Envs used in these studies could impact the level of observed synergy. Further work will be needed to test this conjecture, but the mechanism might be particularly relevant for understanding the wide variety of synergy profiles for clinical HIV-1 isolates in the aforementioned SCH-C/T20 combination study (47). Our results showed that the level of C37 resistance conferred by the V549E substitution depended on CoRA concentration.…”

“…Although some reports have shown strong synergy between FIs and CoRAs (or coreceptor-binding proteins such as RANTES (regulated on activation normal T cell expressed and secreted) or monoclonal antibodies) (43)(44)(45), a number of studies have revealed only weak synergy or additivity between these two inhibitor classes (31,45,46). In one study exploring combinations of CoRA SCH-C and T20 on activated peripheral blood mononuclear cells (PBMCs), three of six CCR5-tropic clinical HIV-1 isolates showed little or no synergy at all inhibitor concentrations, whereas the others showed strongly dose-dependent synergy (47). Here, we investigated the origins of this variability by exploring the inhibitory properties of different CoRA/FI combinations against different Env variants.…”

Enfuvirtide Resistance Mutations: Impact on Human Immunodeficiency Virus Envelope Function, Entry Inhibitor Sensitivity, and Virus Neutralization

“…For example, coreceptor inhibitors reduce the rate of membrane fusion by reducing coreceptor availability, which in turn results in prolonged exposure of the ENF-binding site. The interplay between receptor binding and the exposure (from CD4 binding) and ultimate loss (after coreceptor binding) of the ENF binding site likely accounts for the ability of entry inhibitors to synergistically inhibit HIV infection in vitro (45,46). Since we have found that resistance to ENF need not impact sensitivity to other entry inhibitors, the rationale for combination entry inhibitor therapy is strengthened.…”

Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains

“…These findings suggest a new strategy for treatment of patients who have failed to respond to first-generation drugs. It has been reported that the combination of T20 with PRO 542 (a CD4-based HIV-1 entry inhibitor targeting gp120) or AMD3100 (a CXCR4 antagonist) or SCH-C (a CCR5 antagonist) results in strong synergistic anti-HIV-1 activity (42,53,54). Since it is well known that the combination of two drugs with different mechanisms of action or target sites may lead to synergism (9), it is understandable that combining T20 with other HIV entry inhibitors targeting gp120 or coreceptors FIG.…”