2. Academic Validation
  3. Synthesis and structural insights into the binding mode of the albomycin δ1 core and its analogues in complex with their target aminoacyl-tRNA synthetase

Synthesis and structural insights into the binding mode of the albomycin δ1 core and its analogues in complex with their target aminoacyl-tRNA synthetase

  • Bioorg Med Chem. 2020 Sep 1;28(17):115645. doi: 10.1016/j.bmc.2020.115645.
Bharat Gadakh 1,  Gaston Vondenhoff 2,  Luping Pang 3,  Manesh Nautiyal 1,  Steff De Graef 4,  Sergei V Strelkov 5,  Stephen D Weeks 6,  Arthur Van Aerschot 7
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1041, B-3000 Leuven, Belgium.
  • 2 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1041, B-3000 Leuven, Belgium; Roche Diagnostics GmbH, DXRESA7G6164, Staffelseestrasse 2-8, 81477 Munich, Germany(e).
  • 3 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1041, B-3000 Leuven, Belgium; Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 822, B-3000 Leuven, Belgium.
  • 4 Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 822, B-3000 Leuven, Belgium; OrthogonX, Gaston Geenslaan 1, 3001 Leuven, Belgium(e).
  • 5 Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 822, B-3000 Leuven, Belgium.
  • 6 Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 822, B-3000 Leuven, Belgium; OrthogonX, Gaston Geenslaan 1, 3001 Leuven, Belgium(e). Electronic address: sweeks@orthogontherapeutics.com.
  • 7 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1041, B-3000 Leuven, Belgium. Electronic address: arthur.vanaerschot@kuleuven.be.
PMID: 32773091 DOI: 10.1016/j.bmc.2020.115645
Abstract

Despite of proven efficacy and well tolerability, albomycin is not used clinically due to scarcity of material. Several attempts have been made to increase the production of albomycin by chemical or biochemical methods. In the current study, we have synthesized the active moiety of albomycin δ1 and investigated its binding mode to its molecular target seryl-trna synthetase (SerRS). In addition, isoleucyl and aspartyl congeners were prepared to investigate whether the albomycin scaffold can be extrapolated to target other aminoacyl-tRNA synthetases (aaRSs) from both class I and class II aaRSs, respectively. The synthesized analogues were evaluated for their ability to inhibit the corresponding aaRSs by an in vitro aminoacylation experiment using purified Enzymes. It was observed that the diastereomer having the 5'S, 6'R-configuration (nucleoside numbering) as observed in the crystal structure, exhibits excellent inhibitory activity in contrast to poor activity of its companion 5'R,6'S-diasteromer obtained as byproduct during synthesis. Moreover, the albomycin core scaffold seems well tolerated for class II aaRSs inhibition compared with class I aaRSs. To understand this bias, we studied X-ray crystal structures of SerRS in complex with the albomycin δ1 core structure 14a, and AspRS in complex with compound 16a. Structural analysis clearly showed that diastereomer selectivity is attributed to the steric restraints of the active site of SerRS and AspRS.

Keywords

Albomycin; Albomycin analogues; Aminoacyl-tRNA synthetase inhibitors; Natural product synthesis; Serine-tRNA synthetase; Structural analysis; X-ray crystallography.

Figures
Products