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Subject: DBT proposal Cone snail outline (fwd) View full header 

From: "P.Balaram" <> 

Date: Sat, May 4, 2002 2:05 pm 
To: Prajna Pal <> 

Pi. print. 


- Forwarded message - 

Date: Sat, 4 May 2002 10:45:28 +0530 
From: K S Krishnan < > 



Subject: DBT proposal Cone snail outline 

I got your mail about CSIR . This is some blurb I had put together ..we 
can discuss when I am in Bangalore..I will be there tonight and will 
come home or lab tomorrow around 10:00 AM ..will call and fix time with 

More than 500 species of predatory Conus have been identified; in 

the Indo pacific region. Each of these marine snails produces its own 
mixture of deadly conotoxins. The toxins are used by these slow moving 
animals to catch their prey which may be marine worms, fishes and other 
molluscs. The need for fast acting components for success in their 
predation has made these snails evolve cabals of potent and highly 
specific neurotoxins to exploit prey niches. The exquisite specificity 
of these toxins in mammalian systems that have pharmacologically diverse 
neuronal macromolecules allows them to block the perception of pain in 
animals, leaving normal sensory signals intact. Similarly highly 
specific drugs targeted to neuronal receptors with no side effects due 
to cross reactivity can be expected to be discovered. 

CU <o c 


Dr. Baldomero Olivera pioneered the research in these Contoxins. The 
experimental drug Ziconitide, which is a thousand times more potent than 
morphine in relieving chronic pain -- without any side effects, was 
developed by the Neurex Corporation starting from Dr Olivera's first 
major discovery the /z conotoxin. It is a potential treatment for 
intractable pain because it helps some patients who were unresponsive 
even to large doses of morphine. The drug, synthesized to match a toxin 
produced by Conus magus, is now in Phase III clinical trials involving 
patients who have AIDS, cancer, or severe non-malignant pain. It is 
hoped that Ziconitide or SNX-111 will not cause tolerance, in which 
patients require ever-larger doses of a drug to experience the same 
effects. An interesting information is that this single compound was 
instrumental in fetching a price of several hundred millions of dollars 
for Neurex Corporation when it was bought by Elan recently. 

Other Conus species may soon join C. magus in the pharmacopoeia of 
neuromedicine. Dr. Olivera and and colleagues in collaboration with 
Cognetix Corporation of Salt Lake City, are testing therapeutic effects 
of a peptide from the marine snail, C. radiatus, in animal models for 
epilepsy. The peptide, called conantokin-R, appears to offer powerful 
protection against seizures but causes few of the behavioral side 
effects that trouble some users of conventional treatments. Recent 
studies of a toxin produced by the snail, Conus textile is approaching 
the end of the research pipeline. 

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With more than 100 conotoxins now characterized, and perhaps thousands 
more awaiting detection or evaluation, those who have joined the fray 
expect to discover a bounty of potential conotoxin-based drugs in coming 

But very much more than all that these toxins may prove to be a boon for 
the neuroscientist, the structural biologist and evolutionary biologist 
to probe deeper fundamental questions in biology. 

Groups in Australia, Israel , China , Philippines and even Singapore 
have joined the fray and in Australia at least two commercial ventures 
have been started up with academic and biotech industry participation. 

Interestingly to us a large fraction of the cone snail species are found 
in the coastal regions of India and are unique to this coast. The very 
fact that they are different species, in view of the evolutionary 
strategies inherent in the development of toxin cabals in these animals, 
promises a bounty of unprecedented value in terms of therapeutic drugs 
if this vast natural richness is exploited judiciously and exclusively. 
Our great advantage over all competition is this richness of species 
from Laccadives to Andamans and all of southern Indian coasts. The 
Marine Biology Center of the Annamali University at Porto Novo is 
perhaps the only institution from where a beginning on work on cone 
snail biology was started but which has petered away in the past few 
years. Some of the expertise in that institution in collecting and 
identifying is hoped to be input in to this project. This will be 
combined with strong tradition in structure determination of small 
peptides and ability to synthesise and modify that is the 
internationally proven strength of the Bangalore investigators. Bombay 
has built a tradition of neurobiological investigations both behavioural 
and electrophysiological studies which are crucial for the 
Pharmacological characterisation of the activities of peptides hoped to 
be isolated. These and Cell biological studies to be done at Bombay will 
be of value to understanding mechanisms of action of these molecules. In 
addition Molecular biological studies will in the long term circumvent 
the need for collecting snails and while at the same time help 
understand the diversity of these toxins. The investigators have proven 
expertise in all these areas. Dr. Baldomero Olivera who pioneered the 
studies in conotoxins is keen on helping the project in basic science 
aspects of conotoxin evolution and biology. Dr. Mani Ramswami of Ufe^h a 
long time collaborator of the PI will be helping in some Neurobiological 
and transgenic studies in Drosophila. These foreign collaborations will 
be undertaken without compromising any commercial advantage that may 
accrue to local institutions and without transfer of material or 
intellectual property rights. In addition we hope to provide a feed back 
to conservation efforts by studying the distribution and biology of cone 
snails, developing tools of molecular taxonomy and ultimately suggesting 
measures to prevent over exploitation of the various species by 
uninformed collectors. 

V ^ 

Obj ectives: 

Identification and structural characterisation of toxic peptides from 
cone snails 

Preliminary Studies: 

In the past few months we have done a survey of coastal regions west 
and east of southern India and identified about 30 species that are 
commonly collected by fishermen and used for making curios in shell 
factories in Rameswaram , Parangipettai etc. We have been able to obtain 
large number of live specimens from fishermen . In fact in the rocky 
caots of TIFR in Bombay we obtain aplenty stranded live specimens of two 
species and have successfully kept hem in aquaaria for over two months 
feeding fish and polychaetes. 

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We have been able to extract peptide fractions from about six species. 
The peptides from two of these species C. Amadis and C. Inscriptus have 
been charcterised MALDI and fractionated by HPLC and sizes determined. 

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One of the peptides has been now completely characterised and structure 
determined. It has potent analgesic activity in mice and kills 
Drosophila on application. This attempt has given us an opportunity to 
standardise the procedures for collection extraction separation and 
analysis and we are ready to expand this on a very large scale to cover 
several species. 

Plan of action: 

In short we will extract peptide fractions from a large number of 
species we can get hold of in reasonable quantities. This we expect to 
be at least ten species. The peptides will analysed by MALDI and 
purified by HPLC . Purified peptides will be used for structure 
determination. MALDI-TOF /MS , peptide chemistry methods will be used 
to determine sequence of purified peptides and NMR methods will be the 
mainstay of structure determination. Biologocal assay will be performed 
in mice and flies to determine toxicity and neuroactivity . 
Pharmacological characerisation and mechanism of action will be 
investigated by electrophysiology and cell biology. 

In addition we have started a modest attempt at making CDNA libraries 
from glands and will develop ways of expressing the products of these 
genes. It will be both probed by consensus conotoxin sequences to 
develop research in expression and regulation of conotoxin genes and 
also we will try expressing peptides for structural studies and use for 
transgenic expression for in vivo functional studies with flies. 

DBT is needed to fund large scale collection expeditions and facilitate 
permits and local help from governmental agencies in Andamas and 
Laccadives as well as coasts Rameshwaram etc. by providing travel and 
local expenses and hiring and research at Bombay and Bangalore 
in the form of cionsumables, equipment and personnel. This detail we 
will work out. 

Download this as a file 

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