Mcl-1 small-molecule inhibitors encapsulated into nanoparticles exhibit increased killing efficacy towards HCMV-infected monocytes

Antiviral Res. 2017 Feb;138:40-46. doi: 10.1016/j.antiviral.2016.11.027. Epub 2016 Nov 30.

Abstract

Human cytomegalovirus (HCMV) spreads and establishes a persistent infection within a host by stimulating the survival of carrier myeloid cells via the upregulation of Mcl-1, an antiapoptotic member of the Bcl-2 family of proteins. However, the lack of potent Mcl-1-specific inhibitors and a targetable delivery system has limited the ability to exploit Mcl-1 as a therapeutic strategy to eliminate HCMV-infected monocytes. In this study, we found a lead compound from a novel class of Mcl-1 small-molecule inhibitors rapidly induced death of HCMV-infected monocytes. Moreover, encapsulation of Mcl-1 antagonists into myeloid cell-targeting nanoparticles was able to selectively increase the delivery of inhibitors into HCMV-activated monocytes, thereby amplifying their potency. Our study demonstrates the potential use of nanotechnology to target Mcl-1 small-molecule inhibitors to HCMV-infected monocytes.

Keywords: Cytomegalovirus; Monocytes; Myeloid cell leukemia 1; Nanoparticles; Small-molecule inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cytomegalovirus / drug effects
  • Drug Discovery
  • Humans
  • Monocytes / drug effects*
  • Monocytes / pathology
  • Monocytes / virology*
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Nanoparticles*
  • Nanotechnology

Substances

  • Antiviral Agents
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein