FLAGShip – A NOVEL DRUG DISCOVERY PLATFORM
The traditional drug discovery pipeline has nearly dried up. This is felt more acutely in cases of drug resistance. The reduced innovation in the biotech and pharma sector have been attributed to the prevailing environment in the large pharmaceutical industries, and technical limitations in identifying new compounds with desirable activity (Cuatrecasas 2006, Jesse and Vederas 2009).
The key question is: In view of emerging diseases and alarming drug resistance, where will the new drugs come from? As a precursor to this grand challenge of finding a needle in the haystack,
2. ORIGIN OF THE IDEA
(i) Why did nature choose a particular region for making proteins?
(ii) Did she sample every possible genomic combination selecting some and rejecting others?
(iii) If not, can we artificially express intergenic sequences into functional peptides and proteins?
(iv) If yes, would such ‘lab-made proteins’ be stable and functional?
(v) What will be the boundary conditions and the best case scenarios of such an approach?
In 2009, we demonstrated for the first time the possibility of making novel genes from
intergenic sequences of E.coli. Historically, people have called these sequences as ‘junk’ DNA /dark matter and so on… Our work demonstrated the possibility of making functional genes and proteins from the intergenic sequences of the E.coli genome. (Dhar et al 2009) [Fig. 1]
In 2010, the European Science Commission (in their report) termed our work potentially groundbreaking. Following this, this work was presented at the US National Science Academy of Sciences (Beijing), IUPAC (Brussels), OPCW (The Hague), IUPAC (Brussels) and so on. The key strength appreciated in our approach was simplicity, scalability, novelty and non-obviousness.
Having provided the proof of the concept, we were emboldened to ask a bigger question: Can
we use this approach to build a novel drug discovery platform. The quest to look for novel genes and proteins from the unexpressed genome led to a novel drug discovery platform.
3. Project FLAGSHIP
For the last five years, we have been building a bioinformatics database of potential genes and proteins originating from intergenic sequences of model organisms (unpublished).
Using this in-house database [Fig 2, below], and initial experimental results, we have built a novel drug discovery platform based on peptides and proteins. The most promising part is that every therapeutic peptide/protein is novel, non-obvious, and patentable.
Through this platform, we have identified several anti-infective, anti-parasitic, anti-cancer and
anti-alzheimer’s peptides and proteins. The initial dataset has led to experimental proof of novel peptides against several promising targets in malaria, breast cancer, leishmania and so on (patent application under process).
This work has led to spinning of Foresight Biotech (currently incubated at JNU). In future, we are planning to make reagents (enzymes, transcription factors, signalling molecules etc) and
therapeutic biomolecules (peptides and proteins) from naturally non expressing genome and
scale up production of molecules towards various applications.
1. Cuatrecasas P. Drug discovery in jeopardy. J. Clin Invest. 2006: 116, 2837- 2842
2. Dhar PK et al. Synthesizing non-natural parts from natural genomic template. J. Biol. Engg. 2009: 3, 2
3. Varughese D, AS. Nair, PK. Dhar. Functional Annotation of Novel Peptides Generated from the non-expressing genome of Drosophila melanogaster. Bioinformation 2016: 12, 202-208
4. Shidhi PR, P Suravajhala, A Nayeema, A S. Nair, S Singh, P K. Dhar. Making novel proteins from pseudogenes. Bioinformatics. 2015: 31,33-9.
5. Raj N, A Helen, N. Manoj, Harish G., V Thomas, S Singh, S Sehrawat, S Seth, AS. Nair, PK. Dhar. In silico study of peptide inhibitors against BACE 1. Sys. Synth.Biol. J. 2015 9: 67-72
6. Joshi M, SV Kundapura, T Poovaiah, K Ingle, PK Dhar. Discovering Novel Anti-Malarial peptides from theNot-coding Genome – A Working Hypothesis. Curr Synth Sys Biol 2013, 1:1
7. Jesse WH Li, John C. Vederas. Drug Discovery and Natural Products: End of an Era or an Endless Frontier? Science 2009: 325, 161-165
8. Synthetic Biology. From Science to Governance. A workshop organised by the European Commission’s Directorate-General for Health & Consumers. 18-19 March 2010, Brussels