Regular paper Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry by targeting gp41 Shuwen Liu a,c , Hong Lu a , Qian Zhao a , Yuxian He a , Jinkui Niu a , Asim K. Debnath a , Shuguang Wu b, T , Shibo Jiang a,c, T a Lindsley F. Kimball Research Institute, the New York Blood Center, 310 E 67th Street, New York, NY 10021, USA b Institute of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China c Anti-Viral Research Center, Southern Medical University, Guangzhou, Guangdong 510515, China Received 18 December 2004; received in revised form 22 February 2005; accepted 23 February 2005 Available online 24 March 2005 Abstract Theaflavin derivatives and catechin derivatives are the major polyphenols in black tea and green tea, respectively. Several tea polyphenols, especially those with galloyl moiety, can inhibit HIV-1 replication with multiple mechanisms of action. Here we showed that the theaflavin derivatives had more potent anti-HIV-1 activity than catechin derivatives. These tea polyphenols could inhibit HIV-1 entry into target cells by blocking HIV-1 envelope glycoprotein-mediated membrane fusion. The fusion inhibitory activity of the tea polyphenols was correlated with their ability to block the formation of the gp41 six-helix bundle, a fusion-active core conformation. Computer-aided molecular docking analyses indicate that these tea polyphenols, theaflavin-3,3V -digallate (TF 3 ) as an example, may bind to the highly conserved hydrophobic pocket on the surface of the central trimeric coiled coil formed by the N-terminal heptad repeats of gp41. These results indicate that tea, especially black tea, may be used as a source of anti-HIV agents and theaflavin derivatives may be applied as lead compounds for developing HIV-1 entry inhibitors targeting gp41. D 2005 Elsevier B.V. All rights reserved. Keywords: Tea polyphenol; HIV entry inhibitor; HIV-1 gp41; Six-helix bundle; Theaflavin 1. Instruction Since the first report of the acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) infection two decades ago, more than 60 million people worldwide have been infected by HIV and over one third have died of AIDS [1]. Since the vaccine is still far away, the development of effective, safe and affordable anti- HIV drugs is critical to save the lives of people who have been and will be infected by HIV. Until now, most of the FDA approved anti-HIV drugs are HIV reverse transcriptase inhibitors (RTIs), including the nucleotide RTIs (NRTIs) and non-nucleotide RTIs (NNRTIs), and protease inhibitors (PIs), except T-20, the first member of a new kind of anti- HIV drugs, HIV entry inhibitors [2,3]. Clinical applications of these drugs in various combinations, known as highly active antiretroviral therapy (HAART), have dramatically reduced the morbidity and mortality of AIDS and have significantly improved life expectancy for HIV positive patients. However, substantial numbers of HIV-infected patients on HAART regimens cannot use the RTIs or PIs due to the emergence of drug-resistant HIV mutants and serious adverse effects. Thus, the development of new classes of anti-HIV drugs targeting different stages of HIV replication, such as HIV entry, integration and maturation, are urgently needed. Catechins and theaflavins are two groups of natural polyphenols found in green tea and black tea, respectively 0304-4165/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2005.02.012 T Corresponding authors. Shuguang Wu is to be contacted at fax: +86 20 8764 4781. Shibo Jiang, Lindsley F. Kimball Research Institute, the New York Blood Center, 310 E 67th Street, New York, NY 10021, USA. Fax: +1 212 570 3099. E-mail addresses: shuguang@fimmu.edu (S. Wu)8 sjiang@nybloodcenter.org (S. Jiang). Biochimica et Biophysica Acta 1723 (2005) 270 – 281 http://www.elsevier.com/locate/bba