title: CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides.
abstract: OBJECTIVE
  The antiviral activity of CD4 miniproteins was evaluated as potential HIV microbicides, using relevant in vitro models.
  
  
  METHODS
  Compounds were tested in a single-cycle HIV-1 pseudovirus assay and against replication competent HIV-1 in co-cultures of monocyte-derived dendritic cells (MO-DC) and CD4+ T cells. Cytotoxic activity was evaluated in an MTT assay.
  
  
  RESULTS
  Monomeric miniproteins (M47 and M48) showed 50% effective concentration (EC(50)) values of 79-105 nM against a subtype B, CCR5 co-receptor-using Ba-L pseudovirus. Higher activity was found for the dimeric miniproteins M48D30, M48D50 and M48D100 (EC(50) between 15 and 30 nM), in contrast to the tetrameric miniproteins M48T30, M48T50 and M48T100 (EC(50) between 107 and 377 nM). The hetero-bivalent miniprotein M48-Hep and miniproteins that targeted the Phe-43 cavity on gp120 (M48-U1, M48-U2 and M48-U3) were highly active, with EC(50) values as low as 2 nM for M48-U1. All miniproteins showed high activity against CCR5 or CXCR4 co-receptor-using subtype B and CRF-01_A/E pseudoviruses. Many early M48-based compounds were much less active against subtype C pseudoviruses, whereas M48-U compounds that targeted the Phe-43 cavity were very active against all pseudoviruses, including subtype C. In MO-DC/CD4+ T cell co-cultures with replication-competent HIV-1 Ba-L, EC(50) values ranged between 13 and 1719 nM depending on the miniprotein, with M48-U1, M48-U2 and M48-U3 again being the most potent. Importantly, the latter compounds completely prevented viral replication by treating the cultures from 2 h before until 24 h after infection, at non-toxic concentrations of 66-6564 nM.
  
  
  CONCLUSIONS
  These novel CD4 miniproteins might constitute a promising class of HIV microbicides.
authors.affiliation: Virology Unit, Department of Microbiology, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Yven
authors.initials: Y
authors.lastname: Van Herrewege
authors.forename: Laurence
authors.initials: L
authors.lastname: Morellato
authors.forename: Anne
authors.initials: A
authors.lastname: Descours
authors.forename: Laetitia
authors.initials: L
authors.lastname: Aerts
authors.forename: Jo
authors.initials: J
authors.lastname: Michiels
authors.forename: Leo
authors.initials: L
authors.lastname: Heyndrickx
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development*; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010455:Peptides / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D010455:Peptides