Venom and Toxin Research Programme

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Research Theme

 

From Venoms to Drugs, From Toxins to Therapeutics

The venoms of animals contain highly active components, the effects of which have yet to be fully explored. The technology platform that has been built over the years under the Venom and Toxin Research Programme (VTRP), coupled with the library of protein and peptides with potential therapeutic usefulness that we have in our possession, will allow us to complete the discovery process of lead candidates in time and to transfer valuable supplementary information to the next discovery steps involving profiling and optimization of lead candidate(s).  The aim of the project is therefore to characterize the animal (snake, scorpion, cone snail) venom components and natural toxins at a molecular level and seek to identify promising compounds amenable to the development of novel human therapeutics.  Using our own discovery tools and resources, and in collaboration with industrial and academic partners whenever possible, we are contributing to the development of new drugs, diagnostic markers and research tools. This strategic research area will lead us to completion of the lead discovery cycle of investigations and will allow the selection of lead candidates for the early development stage of the drug discovery process.  We have so far identified twenty three highly prized peptides with unique medical indications from venom-based proteins with some already under development as therapeutics.

 

 

  • To conduct research in the key areas of inflammation-related diseases such as rheumatoid arthritis, cancer and neurodegeneration.
  • To adopt platform technologies including toxin detection (biosensors and quantum dots) and toxicogenomics (micro-arrays, protein chips).
  • To develop antimicrobial peptides, and inflammation related pathologies, from venoms and toxins, with special interest focused on the role of cytokines, enzymes and their inhibitors in arthritis and neurodegeneration.
  • To continue with the development and commercialization of the patented anti-inflammatory and antimicrobial peptide drugs to generate licensing opportunities.

 

 

Research Areas

 

  • Main theme of research is focused on the potential uses of venoms and toxins of venomous animals for drug discovery including structure function relationship, and screening of animal venoms (snake, scorpion, and spider) for blood coagulation factors, fibrinolysis and platelet aggregation, ion channels, and their inhibitors for therapeutic uses.
  • Toxin detection based on technologies like biosensors and quantum dots, and toxicogenomics and expression studies on gene expression implicated in toxin-induced neurotoxicity through transcription profiling approaches.
  • Pathogenesis of B. Pseudomallei, and development of antimicrobial peptides from venoms and toxins.
  • Inflammation related pathologies, with special interest focused on the role of cytokines, enzymes and their inhibitors in arthritis and neurodegeneration.
  • Development of lead compounds (anti-inflammatory and anti-microbial peptides) through pre-clinical evaluation including pharmacology, toxicology, pharmacokinetics, formulation chemistry and pre-clinical proof of concept studies.
  • Anti-inflammatory peptide loaded microemulsion gel formulation as potential therapeutic for post-operative adhesion.

 

 

Programme Highlights

 

Collaborative Research Projects

 

  1. Proteomics International Pty Ltd (Australia): Assess therapeutic peptides for biological activity.
  2. Alexander Fleming Biomedical Sciences Research Center (Greece): Assess the therapeutic efficacy of the biopeptide on rheumatoid arthritis and bone diseases, with transgenic mouse lines and designed peptides
  3. ProTherapeutics (Singapore): Examine safety and efficacy of the peptide analogue.  
  4. Institute of Bioengineering and Nanotechnology (A*STAR): Development of platform technology for toxin detection.
  5. Institute of Chemical and Engineering Sciences (A*STAR): Discover the ancillary action of the Microemulsion gel to the PIP-18 in reducing post-operative adhesions.
  6. Eli Lilly and Company: Lilly Phenotypic Drug Discovery Initiative

 

Research Achievements

 

Patents granted:

  1. US Patent N0: US7422890 (2008). Gopalakrishnakone, Ponnampalam, Thwin, Maung-Maung,  Jeyaseelan, Kandiah,  Armugam, Arunmozhiarasi. Therapeutic and prophylactic agents and methods of using the same.
  2. US Patent No: US20070037253 (2007). Gopalakrishnakone, Ponnampalam, Thwin, Maung-Maung,  Sato, Kazuki.  Methods and compositions for treatment of arthritis and cancer.
  3. US Patent No: US20070128179 (2007) Gopalakrishnakone, Ponnampalam, Samy, Ramar Perumal. Phospholipase(s) and use(s) thereof.
  4. European Patent Office No: EP1839046. (2007) GAO, Zhiqiang, GOPALAKRISHNAKONE, Ponnampalam, LE, Van Dong,  FANG, Xie. Enzymatic electrochemical detection assay using protective monolayer and device therefore.
  5. US Patent No: US7176281. (2007) Gopalakrishnakone, Ponnampalam, Thwin, Maung-Maung, Ong, Wei-Yi, Sato, Kazuki. Phospholipase A2-inhibitory peptide with anti-arthritic and neuroprotective activities. 
  6. Patents pending: Bactericidal venom-based polypeptides for treatment of Staphylococcus aureus skin infections and wound healing (ILO Reference 09126N).

 

Awards:

  1. ASEAN University Network Distinguished Scholar - Feb 2007

  2. President (Elect), International society on Toxinology - 2007

 

 

Key Representative Publications

 

  1. Thwin MM, Douni E, Arjunan P, Kollias G, Kumar PV, Gopalakrishnakone P.  Suppressive effect of secretory phospholipase A2 inhibitory peptide on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice. Arthritis Res Ther. 11:R138. (2009) [E-pub ahead of publication]
  2. Thwin MM, Satyanarayanajois SD, Nagarajarao LM, Sato K, Pachiappan A, Ramapatna LS, Kumar PV, Gopalakrishnakone P. Novel peptide inhibitors of human secretory phospholipase A2 with anti inflammatory activity: solution structure and molecular modelling. J Med Chem 50:5938-50. (2007).
  3. Thwin MM, Douni E, Aidinis V, Kollias G, Kodama K, Sato K, Satish RL, Mahendran R, Gopalakrishnakone P. Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study. Arthritis Res Ther 6, R282-94 (2004).
  4. Aidinis V, Carninci P, Armaka M, Witke W, Harokopos V, Pavelka N, Koczan D, Argyropoulos C, Thwin MM, Moller S, Waki K, Gopalakrishnakone P, Ricciardi-Castagnoli P, Thiesen HJ, Hayashizaki Y, Kollias G. Cytoskeletal rearrangements in synovial fibroblasts as a novel pathophysiological determinant of modeled rheumatoid arthritis. PLoS Genet 1:e48 (2005).
  5. Perumal Samy R, Gopalakrishnakone P, Ho B, Chow VT. Purification, characterization and bactericidal activities of basic phospholipase A (2) from the venom of Agkistrodon halys (Chinese pallas). Biochimie. 90:1372-88. (2008).
  6. Dong le V, Eng KH, Quyen le K, Gopalakrishnakone P. Optical immunoassay for snake venom detection. Biosens Bioelectron. 19:1285-94.(2004).
  7. Nirthanan S, Pil J, Abdel-Mottaleb Y, Sugahara Y, Gopalakrishnakone P, Joseph JS, Sato K, Tytgat J. Assignment of voltage-gated potassium channel blocking activity to kappa-KTx1.3, a non-toxic homologue of kappa-hefutoxin-1, from Heterometrus spinifer venom. Biochem Pharmacol. 69:669-78.(2005).
  8. Pachiappan A, Thwin MM, Keong LW, Lee FK, Manikandan J, Sivakumar V, Gopalakrishnakone P. ETS2 Regulating neurodegenerative signaling pathway of human neuronal (SH-SY5Y) cells exposed to single and repeated low-dose sarin (GB).Chem Res Toxicol 22: 990-6. (2009).
  9. Bringans S, Eriksen S, Kendrick T, Gopalakrishnakone P, Livk A, Lock R, Lipscombe R. Proteomic analysis of the venom of Heterometrus longimanus (Asian black scorpion). Proteomics 8:1081-96. (2008).
  10. Lok SM, Gao R, Rouault M, Lambeau G, Gopalakrishnakone P, Swaminathan K. Structure and function comparison of Micropechis ikaheka snake venom phospholipase A2 isoenzymes. FEBS J. 272:1211-20. (2005)

 

 

Member(s) of Programme


Programme Coordinator:

Prof P Gopalakrishnakone


Research Fellow:

Dr Maung Maung Thwin
Dr R. Saminathan
Dr Gao Rong
Dr P. Saravanan

 

Research Assistant:

Dr R Perumal Samy
Mr Feng Luo

 

 

Contact Details


Professor P Gopalakrishnakone
Department of Anatomy & Venom And Toxin Programme (VTRP)

National University of Singapore
Yong Loo Lin School of Medicine
4 Medical Drive
National University of Singapore
Singapore 117597
Tel :  6516 3207
Fax : 6778 7643
Email : antgopal@nus.edu.sg