Current Projects

The company’s business is focused on the discovery and development of novel lead structures based on cyanobacterial natural products. Using its proprietary strain collection, Cyano Biotech identifies novel leads, optimizes their pharmacological activities by proprietary techniques and finally generates recombinant microbial production systems. Beside its own drug discovery program, Cyano Biotech collaborates with international pharmaceutical and biotech companies.

Microcystins as antitumor agents

Microcystins, rather known as hepatotoxins produced by cyanobacteria, are currently studied for their potential as leads for anticancer drug development. They potently inhibit the eukaryotic protein phosphatase families PP1 and PP2A. Microcystins display their toxicity after transporter-mediated uptake by the cell. Three human proteins are thought to be able to mediate this uptake, the organic anion transporting polypeptides OATP1B1, OATP1B3, and OATP1A2. Liver cells express OATP1B1 and OATP1B3 transporters and are thus able to absorb microcystins from the blood, resulting in a pronounced liver toxicity of microcystins. OATP1B3 is also expressed in hepatocellular carcinoma cells (HCC) as well as gastrointestinal and lung tumors. Recent data offer support that the OATP1B3 protein is also expressed in a significant percent of breast and colon tumors. Interestingly, compared to OATP1B1, OATP1B3 is found only in low abundance in liver cells. Thus selectivity that favors OATP1B3 over OATP1B1 leads to a decreased hepatic clearance / toxicity and an increased uptake in OATP1B3-expressing tumors, creating a therapeutic window for the respective compound.

In addition to the cancer cell selectivity, microcystins are of interest as possible anti-cancer drugs because they act by a novel mechanism of action (phosphatase inhibition) and the cell death they cause is independent of apoptotic pathways.

Since about 100 naturally occurring microcystins with variations in the seven constituting amino acids are known and many more structures are not described yet, there is high potential for isolating variants with unique properties. In fact, in our initial screening of 20 microcystins, we have found four microcystin structural variants with an IC50 in the low nanomolecular range and with transporter selectivity that favors OATP1B3 over OATP1B1 by a factor of more than ten. Some of these microcystin variants have not yet been described in the literature.

Testing of further microcystin variants, the elucidation of their structures and the deduction of structure-activity relationships will enable us to find and create more selective and potent compounds.


Microginins as ACE inhibitors

Microginins are linear, non-toxic lipopeptides and vary in length from four to six amino acids. They all have the unusual amino acid derivative 3-amino-2 hydroxy- decanoic acid (Ahda) at the N-terminus in common and represent a broad group of unusual lipopeptides with an inhibitory effect on the angiotensin-converting enzyme (ACE). They are therefore potential agents to treat hypertension and associated diseases such as chronic heart failure and diabetic nephropathy. The compounds also inhibit further zinc metalloproteases like e.g. leucin aminopeptidases.

Microginins are non-ribosomally synthesized by a multi-enzyme complex – the microginin synthetase that was recently discovered by Cyano Biotech. The company identified and sequenced the encoding microginin synthetase genes of the cyanobacterium Microcystis aeruginosa for the first time. Based on the DNA sequence, Cyano Biotech developed the following applications that were covered by a US and EP patent.

  • Easy and effective methods to identify microginin-producing strains as well as novel microginin analogs and microginin-like structures (oscillaginins, nostoginins, cyanostatins) in cyanobacteria
  • Biocombinatorial methods to generate novel non-natural microginins optimizing the ACE- inhibitory effect
  • Heterologous expression of the genes in order to produce natural and novel microginins in higher yields.


cultures



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