A treasure trove of therapeutics?

February 6, 2021 0 By FM

Cyanobacteria are promising but still unexplored natural resources offering a wealth of chemicals for the discovery of pharmaceutical compounds and new drugs. They have gained a lot of attention in recent years as a rich source of biologically active compounds with antiviral, antibacterial, antifungal and anticancer activities. They are also used in the production of secondary metabolites including exo-polysaccharides,
vitamins, toxins, enzymes and pharmaceuticals. Scientists are also hopeful that future research could genetically modify existing strains to ensure maximum production of the desired products.

Unique microorganisms

Cyanobacteria are a unique class of microorganisms which are gram-negative and photosynthetic. They are prokaryotes which have fossil records from 3.3 to 3.5 billion years ago and are still among the most successful organisms on earth. Cyanobacteria have many names, such as cyano-prokaryotes, cyanophytes or blue-green algae. These names are derived from the fact that cyanobacteria have a blue-green pigment called C-Phycocyanin.

Genome sequencing studies of cyanobacteria show significant diversity and novelty of genes responsible for bioactive proteins, ribosomal and non-ribosomal peptides, and peptide-polyketide hybrid molecules. The presence of non-ribosomal peptide synthetase and polyketide synthetase genes reveals the potential for finding new varieties of drugs from these organisms. It is well known that the non-ribosomal peptide synthetase-polyketide synthetase system produces a diverse family of compounds having biological and pharmacological properties. Cyanobacteria produce a wide variety of bioactive compounds, which are described below.

Cyanobacterial drugs for AIDS

The anti-HIV treatment currently in use (Highly Active Antiretroviral Tri-Therapy) has been proved to be toxic. So presently some cyanobacterial compounds are suggested for the treatment of HIV. The most significant among them are Spirulan and Ca-spirulan from Spirulina sp. These compounds showed potent and broad-spectrum activity against HIV-1, HIV-2, Haemophilus influenzae, and a series of other enveloped viruses. These sulfated polysaccharides inhibit the reverse transcriptase activity of HIV-1 (like azidothymidine) and prevent the virus from attaching to the cell. They also inhibit the fusion between HIV-infected and HIV-uninfected CD4 lymphocytes, a mechanism that greatly enhances viral infectivity. These compounds have advantages over other sulfated polysaccharides because of reduced anti-coagulant properties. Nostoflan, an acidic polysaccharide from Nostoc flagelliforme which exhibits potent virucidal activity against herpes simplex virus-1, is also noteworthy.

Cyanobacterial Drugs Against Viral Diseases

A number of screening campaigns have identified cyanobacteria as a potential source for antiviral compounds. More detailed studies have been done on sulfoglycolipids and lectins.

Sulfoglycolipids : Antiviral sulfoglycolipids such as sulfolipid 1 were isolated from the genera Lyngbya, Phormidium and Scytonema and also identified in Anabaena, Calothrix, and Oscillatoria. These compounds as well as structurally related acylated diglycolipids from Oscillatoria and Phormidium show inhibition of the human immunodeficiency virus (HIV-1) via inhibition of the DNA polymerase function of HIV-1 reverse transcriptase. Esterification of the free hydroxyl groups of the sulfosugar with further fatty acids leads to a significant decrease in activity. The presence of the fatty acid chains of the sulfoglycolipids is mandatory for activity.

Lectins : Cyanovirin-N, a peptide lectin isolated from Nostoc ellipsosporum, targets N-linked, high-mannose glycans, and was found to be a fusion inhibitor, preventing infection with all HI virus types. Cyanovirin-N is strongly active against influenza A and B, respiratory syncytial virus, enteric viruses, and several coronaviruses. The compound is found to be readily expressive in E. Coli. Recently, another anti-viral lectin by the name microvirin has been isolated from Microcystis aeruginosa and another with similar properties, scytovirin, from Scytonema varium.

Cyanobacterial Drugs Against Cancer

There is an urgent need for new anticancer drugs because of increasing resistance towards existing ones. New types of cancers like glioblastoma also are increasing rapidly. The screening of cyanobacterial extracts for new anticancer compounds was initiated in Moore’s laboratory under Oregon State University and also in the Gerwick laboratory at the University of Hawaii during the 1990s. Cryptophycins represent a major class of potent anticancer agents produced by the cyanobacteria. Cryptophycin 1 was isolated from Nostoc sp. GSV224 in Moore’s lab. It was found to be 100–1000 times more potent than human nasopharyngeal cancer and colorectal cancer. It also exhibits activity against adriamycin-resistant breast cancer and lung cancer cell lines. There are several analogs of cryptophycin either naturally isolated or chemically synthesized which are under different stages of human trials.

Marine cyanobacterial compounds can target tubulin or actin filaments in eukaryotic cells, making them an attractive source of anticancer drugs. Curacin A and Dolastatin 10, have been in preclinical and/or clinical trials as potential anticancer drugs. These molecules have also served as models for the development of synthetic analogues, such as TZT-1027, ILX-651, and LU-103793, for the treatment of different types of cancers. The antitumor activity of TZT-1027 (Soblidotin), a synthetic derivative of dolastatin 10, was found to be superior to paclitaxel and vincristine and it is currently undergoing phase I trial for treating solid tumours. The third generation dolastatin 15 analogue, ILX-651 (or Tasidotin), is another antitumour agent currently undergoing phase II trials.

Cyanobacterial drugs as Protease Inhibitors

Five classes of protease inhibitors have been reported from the toxic genera of cyanobacteria: they are micropeptins, aerugenosins, microginins, anabaenopeptins and microverdins. Serine protease inhibitors of micropeptin type are the most common inhibitors from cyanobacteria with more than fifty compounds. Some cyanopeptolins are specific inhibitors of serine proteases, including elastase, which is of critical importance in a number of diseases like lung emphysema, which is mediated by excessive action of elastase. Furthermore, it has been proposed that unphysiologically high levels of elastase activity are involved in myocardial damage and may cause a particular form of psoriasis. Cyanopeptolins are subjected to inhibition assays with commercial proteases, which are of medicinal relevance, like trypsin, thrombin, plasmin, papain and elastase. Recently, banyaside A and B was
found to be the trypsin and thrombin inhibitor.

Cyanobacterial drugs Against Protozoa

Many compounds active against the malarial parasite Plasmodium as well as other protozoan parasites such as Trypanosoma (Sleeping Sickness or Chagasʼ disease) or Leishmania (leishmaniasis) have been reported from cyanobacteria. However, many compounds with antiprotozoal activity have cytotoxicity, limiting their usability as drug leads. The ribosomal cyclic peptide Aerucyclamide B from M. aeruginosa is the most active antiplasmodial compound isolated from cyanobacteria to date. Balgacyclamides, isolated from a different M. aeruginosa strain also show a comparable activity. The linear depsipeptide viridamide A from Oscillatoria nigroviridis, showed activity against the parasites Plasmodium falciparum, Trypanosoma cruzi and Leishmania mexicana. Several compounds with antiprotozoal, but at the same time cytotoxic activities, have been described.

It is beyond doubt that cyanobacteria have the potential for expanded utilization in drug discovery. Cyanobacterial secondary metabolites may constitute a prolific source of
new pharmaceuticals. Yet, exploitation of the cyanophycean species has been hampered by a number of issues related to their handling. The relative disregard of cyanobacteria compared with other microbial sources has made them attractive sources of novel drugs. It is worth underlining that the pharmaceutical potential of cyanobacteria deserves more scientific attention. Cyanobacterial strains from still unexplored and extreme habitats can serve as good candidates for new drugs. However, any effort in this direction demands an interdisciplinary approach in research, integrating novel technologies with chemo-taxonomical literature from the past.