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. 2014 Feb 13;5(2):133-137.
doi: 10.1021/ml400370w.

Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc

Shigehiro Asano  1 , Julia Gavrilyuk  1 , Dennis R Burton  2 , Carlos F Barbas 3rd  1
Affiliations

Preparation and activities of macromolecule conjugates of the CCR5 antagonist Maraviroc

Shigehiro Asano et al. ACS Med Chem Lett. .

Abstract

CCR5 antagonists are among the most advanced approaches in HIV therapy and may also be relevant to treatment of graft-versus-host disease and Staphylococcus aureus infection. To expand the potential of the only approved CCR5 antagonist, Maraviroc, we studied derivatives that would enable functional linkage of Maraviroc to long-lived carriers. Through targeted synthesis, we discovered an effective linkage site on Maraviroc and demonstrate the potential of these derivatives to prepare potent chemically programmed antibodies and PEGylated derivatives. The resulting compounds effectively neutralized a variety of HIV-1 isolates. Both chemically programmed antibody and PEGylation approaches extend the neutralization activity of serum circulating Maraviroc. Derivation of a successful conjugation strategy for Maraviroc should further enable its use in chemically programmed vaccines, novel bispecific antibodies, and topical microbicides.

Keywords: CCR5 antagonist; Chemically programmed antibody; Maraviroc; PEGylation.

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Figures

Figure 1
Figure 1
Schematic representations of mechanism of HIV-1 infection of a host cell and inhibition of the viral entry by CCR5 antagonists.
Figure 2
Figure 2
Structure of Maraviroc (1) and linker-attached Maraviroc (2a, 2b, and 3).
Scheme 1
Scheme 1. Syntheses of the cpAbs
Reagents and conditions: (a) S21, THPTA, CuSO4, sodium ascorbate, H2O, t-BuOH, rt, 2 h, 4 100%, 5 67%; (b) mouse mAb 38C2, 100 mM PBS solution (pH 7.4), rt, 2 h.
Scheme 2
Scheme 2. Synthesis of the PEGylated Compounds
Reagents and conditions: (a) S22, THPTA, CuSO4, sodium ascorbate, H2O, tert-BuOH, rt, 2 h, 82%; (b) TFA, CH2Cl2, rt, 1 h, quant; (c) SUNBRIGHT ME-050AS, ME-400AS, or PTE-400HS, DMF, rt, 3 h, 10, 46%, 11 82%, 12 92%, 14, 92%.
Figure 3
Figure 3
Binding of mAb 38C2, mAb conjugates 6 and 7 and positive control mAb 2D7 to (A) HeLa cells, which do not express CCR5, and to (B) TZM-bl cells, which are CCR5-positive, by FACS: mAb 38C2 (pink), secondary antibody (light blue), mAb 2D7 (orange), compound 6 (blue), compound 7 (light green), cell only (red).
Figure 4
Figure 4
Evaluation of inhibition of HIV-1 replication in CCR5-positive cells by Maraviroc 1, mAb conjugate 7, and PEGylated compound 12: clade A 92RW020 (red line), clade B JR-FL (blue line), clade B YU-2 (black line), and clade C MGC26 (green line). All tests were performed in duplicate.
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