Fishing in Nature’s Molecular pools

posted Mar 22, 2016, 2:04 AM by SRamachandran Igib

Fishing in Nature’s Molecular pools

Nature is a treasure trove of potential drugs. The human world is thriving with diseases and applications of every kind. How do we mix and match? Where do we begin our search? We could, for example, start with 100s of different cell lines and begin our test in a systematic manner, cataloging them as we go. Or we could take a bag full of tissues and expose them to the drugs all at once! And here we bring you, the zebrafish screen! A whole organism screen with hundreds of transparent larvae, where the tissues are tagged with fluorescent proteins so you can visually inspect their size, shape, growth and death. Zebrafish embryos offer a first-stop-screening for many organ systems at once. So, can we use zebrafish and go rummaging in the natural world for more and more drugs?

Is there a why not? Let us take the example of the wonder-drug Taxol (now Paclitaxel), a highly successful treatment for various kinds of cancer. Taxol was discovered in the 1960s as part of a US government initiative to find treatments for cancer from the natural world. So, where was the problem? Taxol came from the bark of the Pacific Yew tree, not a commonly found species; and 12 trees had to be killed to yield 1 gm of Taxol!

So, what is the alternative? What if we could synthesize compounds found in the nature? It is not as easy as it sounds. The chemical space that is currently being explored by synthetic routes for drug discovery is but a tiny one. Natural products are complex, multi-ringed structures, very intractable to synthesis in the laboratory. But by bringing the possibility of synthesis to structures inspired by nature we could find a middle ground to play.

As part of efforts that started 9 years ago at bringing together chemists and biologists we recently embarked on this project with the synthetic chemist Dr D Srinivasa Reddy, at the CSIR-NCL. Dr Reddy’s lab offered us a bag full, or rather box full of vials with synthetic products inspired from the natural world. We had our own multi-well plates full of zebrafish larvae, colour-coded for heart and liver and vasculature. When the fish met the compounds, many ended in tragedy. But a very small number showed very interesting and tantalizing phenotypes.

Of these, one had a very potent inhibitory affect on the sprouting of new blood vessels, a process called angiogenesis. Angiogenesis is a critical process for development of the organism, since blood vessels are important for the transport of nutrients and oxygen to the rapidly dividing embryonic cells.  So is it critical for the other rapidly dividing cell type that wreaks havoc in our bodies, the cancer cells. We xenografted human cancer cells into the fish embryo to test if the inhibitor will impede their growth. Early fish embryos do not reject such grafts because their adaptive immunity is still developing. These grafted cells secrete growth factors that seduce blood vessels to abandon their straight and narrow path and steer towards the hungry cancer cells. Treatment with our nature-inspired-synthetic molecule could stop them in their tracks, which could lead to tumour growth arrest eventually. 

Perhaps, using a combination of natural product resource, synthetic organic chemistry and zebrafish embryonic assays we maybe able to dive into nature’s treasure trove repeatedly and come up with powerful molecules for the drug cabinet.

Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays.

Muthukumarasamy KM, Handore KL, Kakade DN, Shinde MV, Ranjan S, Kumar N, Sehrawat S, Sachidanandan C, Reddy DS.

Org Biomol Chem. 2016 Jan 27;14(5):1569-78. doi: 10.1039/c5ob01594d.