2. Academic Validation
  3. Molecular binding mode of PF-232798, a clinical anti-HIV candidate, at chemokine receptor CCR5

Molecular binding mode of PF-232798, a clinical anti-HIV candidate, at chemokine receptor CCR5

  • Acta Pharmacol Sin. 2019 Apr;40(4):563-568. doi: 10.1038/s41401-018-0054-2.
Ya Zhu 1 2,  Yan-Long Zhao 1 2 3,  Jian Li 1 4,  Hong Liu 1 4,  Qiang Zhao 1 2 4 5,  Bei-Li Wu 6 7 8 9,  Zhen-Lin Yang 10 11
Affiliations

Affiliations

  • 1 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 5 Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, 100101, China.
  • 6 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 7 University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 8 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 9 Chinese Academy of Sciences Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 10 Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 11 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
PMID: 29941870 DOI: 10.1038/s41401-018-0054-2
Abstract

The Chemokine Receptor CCR5 is an important anti-HIV (human immunodeficiency virus) drug target owning to its pivotal role in HIV-1 viral entry as a co-receptor. Here, we present a 2.9 Å resolution crystal structure of CCR5 bound to PF-232798, a second-generation oral CCR5 Antagonist currently in phase II clinical trials. PF-232798 and the marketed HIV drug maraviroc share a similar tropane scaffold with different amino (N)- and carboxyl (C)- substituents. Comparison of the CCR5-PF-232798 structure with the previously determined structure of CCR5 in complex with maraviroc reveals different binding modes of the two allosteric antagonists and subsequent conformational changes of the receptor. Our results not only offer insights into the phenomenon that PF-232798 has higher affinity and alternative resistance profile to maraviroc, but also will facilitate the design of new anti-HIV drugs.

Keywords

CCR5; PF-232798; antagonist; anti-HIV; crystal structure; maraviroc.

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