A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity.
Human immunodeficiency virus (HIV) infection is often accompanied by infection with other pathogens, in particular herpes simplex virus type 2 (HSV-2). The resulting coinfection is involved in a vicious circle of mutual facilitations. Therefore, an important task is to develop a compound that is highly potent against both viruses to suppress their transmission and replication. Here, we report on the discovery of such a compound, designated PMEO-DAPym. We compared its properties with those of the structurally related and clinically used acyclic nucleoside phosphonates (ANPs) tenofovir and adefovir. We demonstrated the potent anti-HIV and -HSV activity of this drug in a diverse set of clinically relevant in vitro, ex vivo, and in vivo systems including (i) CD4⁺ T-lymphocyte (CEM) cell cultures, (ii) embryonic lung (HEL) cell cultures, (iii) organotypic epithelial raft cultures of primary human keratinocytes (PHKs), (iv) primary human monocyte/macrophage (M/M) cell cultures, (v) human ex vivo lymphoid tissue, and (vi) athymic nude mice. Upon conversion to its diphosphate metabolite, PMEO-DAPym markedly inhibits both HIV-1 reverse transcriptase (RT) and HSV DNA polymerase. However, in striking contrast to tenofovir and adefovir, it also acts as an efficient immunomodulator, inducing β-chemokines in PBMC cultures, in particular the CCR5 agonists MIP-1β, MIP-1α and RANTES but not the CXCR4 agonist SDF-1, without the need to be intracellularly metabolized. Such specific β-chemokine upregulation required new mRNA synthesis. The upregulation of β-chemokines was shown to be associated with a pronounced downmodulation of the HIV-1 coreceptor CCR5 which may result in prevention of HIV entry. PMEO-DAPym belongs conceptually to a new class of efficient multitargeted antivirals for concomitant dual-viral (HSV/HIV) infection therapy through inhibition of virus-specific pathways (i.e. the viral polymerases) and HIV transmission prevention through interference with host pathways (i.e. CCR5 receptor down regulation).
Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. jan.balzarini@rega.kuleuven.be
Jan
J
Balzarini
Graciela
G
Andrei
Emanuela
E
Balestra
Dana
D
Huskens
Christophe
C
Vanpouille
Andrea
A
Introini
Sonia
S
Zicari
Sandra
S
Liekens
Robert
R
Snoeck
Antonín
A
Holý
Carlo-Federico
CF
Perno
Leonid
L
Margolis
Dominique
D
Schols
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006561:Herpes Simplex / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008812:Mice, Hairless; D008819:Mice, Nude; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D046509:Tissue Culture Techniques
C586406:6-phosphonylmethoxyethoxy-2,4-diaminopyrimidine; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D007155:Immunologic Factors; D019384:Nucleic Acid Synthesis Inhibitors; D063065:Organophosphonates; D011355:Prodrugs; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors