Natarajan Tamilarasu
Rutgers University
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Featured researches published by Natarajan Tamilarasu.
Journal of Biological Chemistry | 2003
Seong-Woo Hwang; Natarajan Tamilarasu; Karen V. Kibler; Hong Cao; Akbar Ali; Yueh-Hsin Ping; Kuan-Teh Jeang; Tariq M. Rana
Antiretroviral therapy to treat AIDS uses molecules that target the reverse transcriptase and protease enzymes of human immunodeficiency virus, type 1 (HIV-1). A major problem associated with these treatments, however, is the emergence of drug-resistant strains. Thus, there is a compelling need to find drugs against other viral targets. One such target is the interaction between Tat, an HIV-1 regulatory protein essential for viral replication, and trans-activation-responsive (TAR) RNA. Here we describe the design and synthesis of an encoded combinatorial library containing 39,304 unnatural small molecules. Using a rapid high through-put screening technology, we identified 59 compounds. Structure-activity relationship studies led to the synthesis of 19 compounds that bind TAR RNA with high affinities. In the presence of a representative Tat-TAR inhibitor (5 μm TR87), we observed potent and sustained suppression of HIV replication in cultured cells over 24 days. The same concentration of this inhibitor did not exhibit any toxicity in cell cultures or in mice. TR87 was also shown to specifically disrupt Tat-TAR binding in vitro and inhibit Tat-mediated transcriptional activation in vitro and in vivo, providing a strong correlation between its activities and inhibition of HIV-1 replication. These results provide a structural scaffold for further development of new drugs, alone or in combination with other drugs, for treatment of HIV-1-infected individuals. Our results also suggest a general strategy for discovering pharmacophores targeting RNA structures that are essential in progression of other infectious, inflammatory, and genetic diseases.
Advances in pharmacology (San Diego) | 2000
Seongwoo Hwang; Natarajan Tamilarasu; Tariq M. Rana
Publisher Summary There is a great need to find new drugs and treatment strategies. Available HIV drugs inhibit two key enzymes of the virus, reverse transcriptase and protease. Given the pathogenesis of HIV mutants capable of resisting triple-drug therapies, the identification of drugs that target HIV proteins, other than reverse transcriptase and protease, is a high priority for the development of new drugs. HIV-1 is a complex retrovirus that encodes six regulatory proteins, including Tat and Rev, essential for viral replication. Inhibition of Tat and Rev function provides attractive targets for new antiviral therapies. The Tat protein is a potent transcriptional activator of the HIV-1 long terminal repeat promoter element. A regulatory element between +1 and +60 in the HIV-1 long terminal repeat, which is capable of forming a stable stem-loop structure designated trans-activation responsive (TAR), is critical for Tat function. The Tat protein functions as a transcriptional activator, whereas Rev acts as a sequence-specific nuclear RNA export factor. Rev is involved in efficient nuclear export, and hence expression of the various incompletely spliced viral transcripts. The target RNA sequence required for Rev function is called the Rev response element (RRE) and is located within the env reading flame. Additional screening of microbial fermentation extracts was carried out to identify more potent Rev—RRE binding inhibitors. An extract of the fungal solid fermentation culture of Epicoccum nigrum WC47880 was found to inhibit the binding of Rev—RRE. The axis contains two positively acting elements, the Rev protein and its RNA target sequence, the RRE. Scattered throughout the HIV genome in the genes coding for virion structural proteins are CRSs (constitutive repressor sequences) that act in cis to constitutively down-regulate the expression of the messenger RNAs (mRNAs) that contain them. Rev binds to the RRE as a multimer. Evidence indicates that the Rev protein, through its nuclear export signal (NES), binds exportin/CRM1 and Ran guanosine triphosphate (GTP) cooperatively when it is bound to the RRE-containing RNA.
Biochemistry | 1999
Ikramul Huq; Yueh-Hsin Ping; Natarajan Tamilarasu; Tariq M. Rana
Bioorganic & Medicinal Chemistry Letters | 2001
Natarajan Tamilarasu; Ikramul Huq; Tariq M. Rana
Bioconjugate Chemistry | 2002
Venkitasamy Kesavan; Natarajan Tamilarasu; Hong Cao; Tariq M. Rana
Bioorganic & Medicinal Chemistry Letters | 2000
Natarajan Tamilarasu; Ikramul Huq; Tariq M. Rana
Bioconjugate Chemistry | 2006
Hong Cao; Natarajan Tamilarasu; Tariq M. Rana
Nucleic Acids Research | 1999
Ikramul Huq; Natarajan Tamilarasu; Tariq M. Rana
Bioconjugate Chemistry | 2001
Natarajan Tamilarasu; Jing Zhang; Seong-Woo Hwang; Tariq M. Rana
Archive | 2000
Tariq M. Rana; Seong-Woo Hwang; Natarajan Tamilarasu