Sponge microbes, snail venoms offer drug leads

Marine sponges and snails may seem vulnerable and defenseless amid predators and competitors in the sea, yet are among the most successful sea creatures throughout evolution. Sponges are our oldest ancestors, the earliest metazoans (multicellular animals), while snails (mollusks) are the most megadiverse among marine invertebrates. Sponges and snails must have evolved effective means to survive the competitive, often harsh, marine environment. The Philippines, with the world’s richest marine biodiversity, is the best place to study these animals and explore their potential for marine drug discovery and biotechnology.

At the University of the Philippines-Diliman, the UP Marine Science Institute leads the PharmaSeas marine drug discovery program with funding from the Department of Science and Technology. PharmaSeas aims to discover new anti-infective agents produced by microbes found in sponges, and new anti-pain agents from the venoms of turrid snails.

Ecology provides drug leads. Soft-bodied and sedentary sponges are physically defenseless, yet are able to ward off fish from biting them. They grow and compete for space and are not overgrown by other reef dwellers, making use of an arsenal of potent defensive chemicals. Microbes that thrive in sponge tissues could be a source of these chemicals. Microbes can confer an adaptive advantage to the host sponge, since they mutate fast enough to vary the chemicals produced depending on the sponge’s needs. In PharmaSeas, these microbes are isolated from sponges, cultured in the laboratory to produce bioactive compounds, and tested against human infectious, disease-causing agents.

Snails have hard shell covers to defend themselves and the most highly evolved ones such as Conus are aggressive hunters of prey such as fish. Conus and their close cousins called turrids (estimated at 12,000 species worldwide) have a venom apparatus — each producing venom of hundreds of neuropeptides (some narcotic, paralytic, or excitotoxic) to sting, pacify, immobilize and kill their prey! In PharmaSeas, unexplored turrid snails are being studied for the first time — aptly, since the Visayas region is the center of turrid diversity in the world. Deep sea-dwelling turrids are collected in ingenious ways by local fisherfolk and dissected in the field, and venom ducts are extracted and purified in the laboratory to yield new neuroactive peptides.

Drug pipeline for infectious diseases and aging problems filled by PharmaSeas. Marine compounds are potent — it only takes a small amount of the compounds to hit their molecular and cellular targets and achieve the desired biological effect. This is because they possess stereo-specificity (or 3D structure specificity) — something that is still difficult to achieve with most chemically synthesized compounds. Also, they are produced as variants (as a group of one major compound and several minor compounds that are related in chemical structure) and these act in combination (or synergy) on their targets. These properties make marine compounds a rich source of potential drugs.

Bacterial infections such as TB, pneumonia, skin and blood infections, hospital-acquired infections, are on the rise with new drug-resistant strains emerging in the Philippines and worldwide. The drug pipeline is running dry with average time for drug development estimated at 15 years. New strains of influenza and dengue viruses have emerged and there is still no single effective antiviral drug available. PharmaSeas’ microbial compounds are being tested to target these diseases to contribute to the anti-infective drug pipeline.

With increasing lifespan worldwide comes problems associated with aging such as cancer, cancer pain, neuropathic pain and neurodegenerative conditions which have to be managed over long periods. There are very few drugs in the market for these conditions, and most patients eventually develop tolerance or resistance to the current drugs. PharmaSeas offers a marine pharmacological gold mine of numerous unexplored venomous turrids. Focus is on neuropeptides that cause sleep, shaking or hypoactivity in mice and act on certain ion channels and receptors found in nerves and muscles — clues that they inhibit pain mechanisms in humans.

Chemodiversity draws from genetics and biotechnology. In PharmaSeas, compounds are chemically purified and characterized, but the amounts isolated are not always enough for bioactivity testing. Also, not all variants of the compounds (chemodiversity) are produced by the microbes or turrids at all times. But chemical SAR (structure-activity relationship) studies require this wide chemodiversity to identify new drug leads. Genetics and biotechnology offer a way around this problem. In PharmaSeas, genes coding for enzymes that biosynthesize microbial compounds, and toxin genes coding for a wide variety of turrid peptides, are being identified. These genes can be cloned and expressed to produce the compounds in large enough quantities.

Marine drug discovery sustained by biodiversity documentation and conservation. Nature is still the best provider of cures. Biodiversity and biomedical research are closely linked with majority of current drugs coming from nature or modeled after natural compounds. Now climate change poses a serious threat to marine biodiversity. In PharmaSeas, information on marine ecology, taxonomy, microbiology, chemistry, biochemistry, bioactivity and genetics is being compiled in the PharmaSeas database as basis for conservation measures for Philippine marine biodiversity.

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Dr. Gisela P. Concepcion, of the Marine Science Institute, UP Diliman, is PharmaSeas program leader and leads Project 3 (Microbial Culture, Chemistry and Bioassays) and Project 4 (Turrid Venom Extraction, Biochemistry and Bioassays). Dr. Porfirio M. Aliño of the Marine Science Institute, UP Diliman, leads Project 1 (Microbial and Turrid Collection, Ecology, Biology and Database); Dr. Ma. Auxilia T. Siringan, of the Natural Science Research Institute, UP Diliman, leads Project 2 (Microbial Characterization, Culture Optimization for Production of Anti-infective Compounds); Dr. Ameurfina D. Santos (succeeded by Dr. Cynthia P. Saloma), of the National Institute of Molecular Biology and Biotechnology, UP Diliman, leads Project 5 (Turrid Genetics, Molecular Phylogeny and Toxin Genes); and Dr. Arturo O. Lluisma, of the Marine Science Institute, UP Diliman, leads the component of Project 5 on Sponge and Microbial Genetics, Molecular Phylogeny and Biosynthetic Genes. E-mail at [email protected].