A dihydro-pyrido-indole potently inhibits HSV-1 infection by interfering the viral immediate early transcriptional events
Authors: Luc Van Kaer
Durbadal Ojha
Supriya Mondal
Debprasad Chattopadhyay
Umesh C Halder
Gobardhan Das
Paromita Bag
Sekhar Chakrabarty
Aruna Biswas
Ashoke Sharon
Debashis Mitra
Hemanta Mukherjee
Journal: Antiviral Research (2014)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Ethnomedicine; HSV; Immediate-early transcription; LSD1; Ophiorrhiza nicobarica.
Affiliations: ICMR Virus Unit, ID and BG Hospital, General Block 4, 57 Dr. Suresh Chandra Banerjee Road, Beliaghata, Kolkata 700010, India., Virology Laboratory, National Institute of Cholera & Enteric Diseases, Kolkata, India., Department of Applied Chemistry, Birla Institute of Technology, Mesra, Ranchi, India., Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, United States., Department of Microbiology and Immunology, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa., National Centre for Cell Science, Pune University Campus, Ganeshkhind, Pune, India., ICMR Virus Unit, ID and BG Hospital, General Block 4, 57 Dr. Suresh Chandra Banerjee Road, Beliaghata, Kolkata 700010, India. Electronic address: .

Abstract:  In our continued quest for identifying novel molecules from ethnomedicinal source we have isolated an alkaloid 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, also known as Harmaline (HM), from an ethnomedicinal herb Ophiorrhiza nicobarica. The compound exhibited a potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. Further we demonstrated that HM did not interfere in viral entry but the recruitment of lysine-specific demethylase-1 (LSD1) and the binding of immediate-early (IE) complex on ICP0 promoter. This leads to the suppression of viral IE gene synthesis and thereby the reduced expression of ICP4 and ICP27. Moreover, HM at its virucidal concentration is nontoxic and reduced virus yields in cutaneously infected Balb/C mice. Thus, the interference in the binding of IE complex, a decisive factor for HSV lytic cycle or latency by HM reveals an interesting target for developing non-nucleotide antiherpetic agent with different mode of action than Acyclovir. 

Retracted: No

PubPeer comments:
 This paper is part of a set of papers from Department of Microbiology and Immunology, St. Antonius Hospital, Nieuwegein authored by E.M,.BIK, that report an outbreak of infection by E. cloacae with resistance to third-generation cephalosporins, among patients in a neonatal care unit. In this paper authors take samples from the nasopharynx and rectum from all children in the neonatal unit: As written in the paper u201cDuring the outbreak, specimens for surveillance culture were obtained once a week from the nasopharynx and rectum from all children in the neonatal unitu201d. Childrenu2019s are Premature neonates 30 gestational weeks or with severe organ dysfunction. Samples are made without mentioning ethical approval by local authorities. Indeed, ethical section is missing from the manuscript, The section conflict of interest is also missing Could the authors please explain how the research was being performed, without any ethical approval, and parents patients consent. , 
 This is Elisabeth Bik, one of the authors. Happy to respond here. First, I am not sure what the commenter means by  This paper is part of a set of papers authored by me about the outbreak. Can the OP clarify which other papers they mean? There is only one. https: scholar.google.com scholar?hl=en as_sdt=0%2C5 q=%22St.+Antonius+Hospital%22+author%3A%22bik%22 btnG= Secondly, the neonatal sampling was done as part of regular clinical diagnosis and care, to determine the bacterial strain(s) the babies were infected with, and to see to which antibiotics the strain was susceptible. There was no additional samples taken just for the sake of research. This is the regular work that the microbiology department of a hospital performs. The molecular fingerprinting was done months later, after the outbreak had stopped, on de-identified bacterial isolates. This was a retrospective analysis done on de-identified samples taken previously for routine medical tests, not for research. As such, at least in 2002, this was not considered to fall under the Dutch WMO ( Wet medisch-wetenschappelijk onderzoek met mensen ). See: https: www.rijksoverheid.nl binaries rijksoverheid documenten rapporten 2020 02 14 niet-wmo-plichtig-onderzoek-en-ethische-toetsing niet-wmo-plichtig-onderzoek-en-ethische-toetsing.pdf Thirdly, ethical and conflict-of-interest statements were not routinely part of scientific papers back in 2002. But happy to disclose that I was an employee of a hospital, without any conflicts-of-interest. , 
 Perhaps just a coincidence that part of the IHU social-media team tweeted the same concerns at the same time as comment #1 was made. https: twitter.com LeProfessionne9 status 1407716082069217283 , 
 Dear Dr. Bik, To support your claim  As such, at least in 2002, this was not considered to fall under the Dutch WMO ( Wet medisch-wetenschappelijk onderzoek met mensen ). you cite a document published in 2020. How does it prove that it wasn t a requirement back in 2002? On the other hand, I have evidence that informed consent was required in The Netherlands since 1984: https: www.jstor.org stable 3564353 Thank you. , 
 #4 You are misrepresenting what your source says. The 1984 consent requirements **clearly** relate to human experiments, which is not the case here. This oversight on your part could indicate the lack of good faith in your concerns about this paper. If you feel otherwise, I suggest contacting the journal to see if they share your concern. In my opinion there do not appear to be any ethical concerns in this paper. , 
 #4  you cite a document published in 2020. How does it prove that it wasn t a requirement back in 2002? The document includes a retrospective aspect. See Appendix 1 (pages 70 onwards) and the dated footnotes therein. ,