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 hig...
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2013
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oai:doaj.org-article:79294dfe17f5401d86726d90af2e7ff32021-11-18T06:07:52ZA multi-targeted drug candidate with dual anti-HIV and anti-HSV activity.1553-73661553-737410.1371/journal.ppat.1003456https://doaj.org/article/79294dfe17f5401d86726d90af2e7ff32013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23935482/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Human 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).Jan BalzariniGraciela AndreiEmanuela BalestraDana HuskensChristophe VanpouilleAndrea IntroiniSonia ZicariSandra LiekensRobert SnoeckAntonín HolýCarlo-Federico PernoLeonid MargolisDominique ScholsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 7, p e1003456 (2013) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jan Balzarini Graciela Andrei Emanuela Balestra Dana Huskens Christophe Vanpouille Andrea Introini Sonia Zicari Sandra Liekens Robert Snoeck Antonín Holý Carlo-Federico Perno Leonid Margolis Dominique Schols A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| description |
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). |
| format |
article |
| author |
Jan Balzarini Graciela Andrei Emanuela Balestra Dana Huskens Christophe Vanpouille Andrea Introini Sonia Zicari Sandra Liekens Robert Snoeck Antonín Holý Carlo-Federico Perno Leonid Margolis Dominique Schols |
| author_facet |
Jan Balzarini Graciela Andrei Emanuela Balestra Dana Huskens Christophe Vanpouille Andrea Introini Sonia Zicari Sandra Liekens Robert Snoeck Antonín Holý Carlo-Federico Perno Leonid Margolis Dominique Schols |
| author_sort |
Jan Balzarini |
| title |
A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| title_short |
A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| title_full |
A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| title_fullStr |
A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| title_full_unstemmed |
A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. |
| title_sort |
multi-targeted drug candidate with dual anti-hiv and anti-hsv activity. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/79294dfe17f5401d86726d90af2e7ff3 |
| work_keys_str_mv |
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