RIC: Research Interest Comparator

PRADEEPKUMAR, Ph.D.
Affiliation: IIT BOMBAY
Email: pradeep@chem.iitb.ac.in
Home Page: http://www.chem.iitb.ac.in/people/Faculty/prof/pradeepkumar.html
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 Abstract:
Research Interests

Chemical Biology of Nucleic Acids

Design, synthesis and evaluation of novel gene targeting drugs.

The recent completion of the human genome project (HGP) revealed that there are 20,000-25,000 protein-coding genes. However, the experimental and computational annotation of human genome have shown that among the family of 3000 or more disease related genes, only 600-1000 genes can be targeted with small molecule drugs. This small number of genes and their corresponding protein products constitute the real “drug targets” in the human genome. However to find a small molecule drug against those disease related genes/proteins, which is the basis of traditional drug discovery approach, is increasingly difficult and that is clearly evident in the very slow progress being made in this area in recent times. It has been estimated that it takes 15 years of research and billions of US dollars to develop a protein targeting small molecule drug. Therefore, instead of targeting the protein itself if we can target gene (DNA) or the intermediate messenger RNA (mRNA) by a short oligonucleotide complementary to the target sequence, it is possible to stop the protein production. This provides ample opportunity to specifically target any disease causing gene, even if it’s undruggable by conventional medicine. The hypothesis was first validated by using antisense oligonucleotides targeting viral RNAs in 1978. Although enormous amount of research has been devoted to the development of antisense-based drugs, there are still problems remaining in terms of potency, specificity and delivery of these molecules inside cells and tissues. As a result there is an urgent need for employing alternate mechanisms and tools for efficient gene down-regulation. Our research efforts will be focused along this direction where we will be addressing the search for bona fide gene silencing molecules using three different approaches, which have emerged in the last decade: (1) Small interfering RNAs (siRNAs), (2) DNA enzymes, and (3) G-quadruplex stabilizing agents. All the projects are interrelated to each other, and demand a multidisciplinary chemical biology approach utilizing the tools from organic chemistry, biochemistry, biophysics and cell biology.

1)Development of chemically modified small interfering RNAs (siRNAs) as therapeutic agents .

The discovery of RNA interference (RNAi, Nobel Prize 2006), which is a post transcriptional gene silencing mechanism in mammalian cells using small interfering RNA (siRNA) duplexes revolutionized the field of gene targeted drugs in 2001. Unlike the antisense mechanism, RNAi is an evolutionarily conserved natural mechanism and has been shown to be more potent, specific and versatile to the mRNA targets, and thus provides enormous opportunity for rational drug discovery. Within the short span of time four RNAi based drugs have entered in the clinical trials and one is being evaluated in the Phase III stage. Chemist’s intervention is needed for making therapeutically appealing siRNAs for increasing their in vivo stability, potency, delivery and pharmacokinetic properties. However, finding a chemical modification (at the nucleotide level of siRNA) which will impart the required drug-like properties of siRNAs is a daunting task. To address such challenges, our lab will be focusing on the synthesis and evaluation of novel chemically modified siRNAs.

2)Selection and evaluation of novel RNA cleaving DNA enzymes.

Another gene silencing technology that emerged in the last decade is the use of DNA enzymes to cleave disease causing mRNAs. DNA enzymes are catalysts based entirely on DNA molecules and have been identified through a combinatorial biology technique called in vitro selection. In contrast to the action of antisense oligonucleotides or siRNAs, the catalytic activity of DNA enzymes does not require the recruitment of any cellular enzymes. Only cofactor needed for their activity is divalent metal ions such as Mg2+, Ca2+ or Zn2+. We will be employing in vitro selections to identify new enzymes that are more efficient than current ones. The lead sequences from such selection efforts will be fine tuned using chemical modifications in the binding arms and/or catalytic core to impart the exo and endonuclease stability, pharmacokinetic properties and in vivo deliverability.

3)Telomere mediated molecular therapeutics.

Telomere is a DNA-protein complex at the chromosomal ends having hexanucleotide repeats of sequence (TTAGGG) which prevents chromosomal degradation and fusion. The G-rich single stranded sequence at the 3’-end of telomere DNA can adopt varying tertiary structures including G-quadruplexes. In normal cells, after each cell division, the telomere sequence gets shortened and that leads to halting of cell division (senescence) and eventually controlled cell death (apoptosis). However, it has been demonstrated that in 85% of cancer cells an enzyme called telomerase is over expressed, which prevents natural shortening of telomere and leads to cell proliferation. Inhibition of telomerase action is an efficient way to tune back the cancer cells for natural cell death. One prominent strategy that emerged in last decade for telomerase inhibition is the stabilization of G-quadruplex structures of telomere DNA, thus preventing its availability as a primer for telomerase assisted elongation. The main criterion for a potential G-quadruplex stabilizing agent is that it should have high binding selectivity towards the intramolecular G-quadruplex structure of telomere over a DNA duplex structure or other potential quadruplex forming sequences in the genome. Only very few of the previously investigated compounds had shown specific inhibition of telomerase using nanomolar concentration (reflected in EC50 values). Therefore there is a large therapeutic window available for the development of novel G-quadruplex stabilizing agents. We will synthesize new quadruplex stabilizing agents and study their interaction with telomeric DNAs.


Keywords extracted from the abstract: [ eliminated words list ]
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Count Word
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Count Word
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RIC Statistics:
Extraction Method: Keyword Count with Lexical Variants Added
Eliminated words list: MedlinePlus List
Similarity Method: Weighted keyword count
Weighting Method: Term Frequency * Inverse Document Frequency
Database: Medline Updates from current year
Publication Type: All
Score Calculation Method: Cosine Similarity Method
Sort by: Score
Submission date and time: 2-22-2008, 23:37:39
Computation time: 00:00:04

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Last updated: Friday, 22-Feb-2008 23:37:43 CST