title: Mcl-1 small-molecule inhibitors encapsulated into nanoparticles exhibit increased killing efficacy towards HCMV-infected monocytes.
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.
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Burrer
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Auburn
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
authors.forename: Juntao
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Fardokht A
authors.initials: FA
authors.lastname: Abulwerdi
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.affiliation: Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, United States. Electronic address: chang@upstate.edu.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Chan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003587:Cytomegalovirus / Q000187:drug effects; D055808:Drug Discovery; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D053758:Nanoparticles; D036103:Nanotechnology
chemical_list: D000998:Antiviral Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein
keywords: Cytomegalovirus; Monocytes; Myeloid cell leukemia 1; Nanoparticles; Small-molecule inhibitor