Antiviral Research 66 (2005) 137–145 Mesuol, a natural occurring 4-phenylcoumarin, inhibits HIV-1 replication by targeting the NF-B pathway Nieves M´ arquez a , Roc´ ıo Sancho a , Luis M. Bedoya b , Jos´ e Alcam´ ı b , Jos´ e Luis L ´ opez-P´ erez c , Arturo San Feliciano c , Bernd L. Fiebich d , Eduardo Mu ˜ noz a,∗ a Departamento de Biolog´ ıa Celular, Fisiolog´ ıa e Inmunolog´ ıa, Universidad de C´ ordoba, Facultad de Medicina, Avda. de Men´ endez Pidal s/n, 14004 C ´ ordoba, Spain b Centro de Biolog´ ıa Fundamental, Instituto de Salud Carlos III, Crt. Majadahonda a Pozuelo, 28220 Majadahonda, Madrid, Spain c Departamento de Qu´ ımica Farmac´ eutica, Facultad de Farmacia, Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain d Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstr. 5, D-79104 Freiburg, Germany Received 17 November 2004; accepted 21 February 2005 Abstract Coumarins and structurally related compounds have been recently shown to inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. In this study we report that mesuol and isomesuol, two 4-phenyl coumarins, isolated from the tree Marila pluricostata, suppress HIV-1 replication in Jurkat T cells. These coumarins do not affect the reverse transcription and intregration steps of the viral cycle and their antiviral effect is additive with that of azidothymidine (AZT). In addition, mesuol inhibits TNF-induced HIV-1-LTR transcriptional activity by targeting the nuclear factor-B (NF-B) pathway. While mesuol does not prevent either the binding of NF-B to DNA or the phosphorylation and degradation of NF-B inhibitory protein, IB, it inhibits the phosphorylation and the transcriptional activity of the NF-B p65 subunit in TNF-stimulated cells. These results highlight the potential of the NF-B transcription factor as a target for anti-HIV-1 compounds such as 4-phenyl coumarins, which could serve as lead compounds for the development of additional therapeutic approaches against AIDS. © 2005 Elsevier B.V. All rights reserved. Keywords: 4-Phenyl-coumarins; Mesuol; HIV-1; LTR; NF-B 1. Introduction Retrovirus life cycle is commonly divided into two phases; the early phase refers to the steps of infection from cell bind- ing to the viral integration into the cell genome, whereas the late phase begins with the expression of viral genes and con- tinues through the release and maturation of progeny virions. The human immunodeficiency virus type 1 (HIV-1), the eti- ologic agent of AIDS, is a retrovirus that enters permissive cells through cell surface receptors and following viral entry, the HIV-1 RNA genome is reverse transcribed to a double- stranded DNA molecule that enters the nucleus and integrates ∗ Corresponding author. Tel.: +34 957 218267; fax: +34 957 218229. E-mail address: fi1muble@uco.es (E. Mu ˜ noz). into the host chromatin (Frankel and Young, 1998; Nisole and Saib, 2004). The post-integration phase of the viral cycle preferentially occurs in activated cells and is regulated by the collaborative action of the viral regulatory protein Tat (Trans- activator of transcription) and cellular factors interacting with the long terminal repeat promoter (LTR), which determines the extent of HIV-1 gene transcription and the level of vi- ral replication in the infected cells (Gaynor, 1995; Pereira et al., 2000). The HIV-1-LTR promoter is approximately 640 nucleotides long and has binding sites for many cellular tran- scription factors and a cis-activating stem-loop RNA structure called transactivating response element (TAR) that represents the main binding site for the HIV-1 Tat protein (Hauber and Cullen, 1988; Pereira et al., 2000). Through interaction with TAR, Tat recruits the positive transcriptional elongation fac- 0166-3542/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.antiviral.2005.02.006