title: Sennoside A, derived from the traditional chinese medicine plant Rheum L., is a new dual HIV-1 inhibitor effective on HIV-1 replication.
abstract: BACKGROUND
  Despite the availability of effective antiretroviral therapies, drugs for HIV-1 treatment with new mode of action are still needed. An innovative approach is aimed to identify dual HIV-1 inhibitors, small molecules that can inhibit two viral functions at the same time. Rhubarb, originated from Rheum palmatum L. and Rheum officinale Baill., is one of the earliest and most commonly used medicinal plants in Traditional Chinese Medicine (TCM) practice. We wanted to explore TCM for the identification of new chemical scaffolds with dual action abilities against HIV-1.
  
  
  METHODS
  R. palmatum L. and R. officinale Baill. extracts along with their main single isolated constituents anthraquinone derivatives were tested on both HIV-1 Reverse Transcriptase (RT)-associated DNA Polymerase (RDDP) and Ribonuclease H (RNase H) activities in biochemical assays. Active compounds were then assayed for their effects on HIV-1 mutated RTs, integrase (IN) and viral replication.
  
  
  RESULTS
  Both R. palmatum L. and R. officinale Baill. extracts inhibited the HIV-1 RT-associated RNase H activity. Among the isolated constituents, Sennoside A and B were effective on both RDDP and RNase H RT-associated functions in biochemical assays. Sennoside A was less potent when tested on K103N, Y181C, Y188L, N474A and Q475A mutated RTs, suggesting the involvement of two RT binding sites for its antiviral activity. Sennoside A affected also HIV-1 IN activity in vitro and HIV-1 replication in cell-based assays. Viral DNA production and time of addition studies showed that Sennoside A targets the HIV-1 reverse transcription process.
  
  
  CONCLUSIONS
  Sennoside A is a new scaffold for the development of HIV-1 dual RT inhibitors.
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121 Padova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Carli
authors.affiliation: Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121 Padova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Del Vecchio
authors.affiliation: Institute of Medicinal Plant Development (IMPLAD), 151 Malianwa North Road Haidian District, 100193 Beijing, China.
authors.forename: Lijia
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corona
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Nicole
authors.initials: N
authors.lastname: Grandi
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Piano
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Elias
authors.initials: E
authors.lastname: Maccioni
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Distinto
authors.affiliation: Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121 Padova, Italy. Electronic address: cristina.parolin@unipd.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Parolin
authors.affiliation: Department of Life and Environmental Sciences, University of Cagliari, Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy; Genetics and Biomedical Research institute, National Research Council (CNR), Cittadella di Monserrato SS554, 09042, Monserrato, Cagliari, Italy. Electronic address: tramon@unica.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Tramontano
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D008516:Medicine, Chinese Traditional; D010936:Plant Extracts / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D012250:Rheum / Q000737:chemistry*; D016914:Ribonuclease H / Q000378:metabolism; D012676:Senna Extract / Q000494:pharmacology*; D000081226:Sennosides; D013045:Species Specificity; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000880:Anthraquinones; D019380:Anti-HIV Agents; D010936:Plant Extracts; D018894:Reverse Transcriptase Inhibitors; D000081226:Sennosides; D012676:Senna Extract; D019427:HIV Integrase; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: Antiviral activity; Dual inhibitor; HIV-1; Plant extracts; Reverse transcriptase; Sennoside A