Drugs from the Sea

Introduction

To understand the link between defensive mechanisms of sessile sponges and the natural products produced by them as a potential source of pharmaceutical drugs for human diseases, one has to realize the complexity of the marine environment. For example, why should a sponge produce anti-cancer drugs? In the scenario of two encrusting sponges growing such that their surfaces touch, the sponge that will "win" this encounter is the one that produces the chemical most effective at killing the rapidly dividing cells of the neighboring sponge. The ability of a chemical to kill rapidly diving cells is the hallmark of chemotherapy. Anticancer drugs often act by killing the rapidly dividing cells of a tumor but generally do not harm "normal" healthy cells. Based on ideas regarding connection between marine chemical warfare and the application of marine natural products in medicine, numbers of pharmaceutical companies try to develop new drugs by isolating active compounds and trying to synthesize them in laboratories. Knowledge from indigenous groups has been used by scientists to identify exciting new chemicals. One notable example of this is a natural product from Palythoa toxica, a soft coral found in tide-pools in Hawaii. The native groups of these islands knew that this coral produced a poison and would dip their spear tips in the coral before battle. Reports of this poison led to the isolation of a very complex molecule, palytoxin, which was subsequently shown to be one of the most potent toxins known.

Sponge-Derived Secondary Metabolites with Pharmaceutical Potential

The success rate of finding a new active chemical is 500 times higher in marine organisms than from terrestrial sources.

Mariane sponges have proven to be the most prolific source of novel therapeutic agents, with biomedical action superior to that of existing pharmaceuticals. They have held promise for the development of new medicines since the discovery of antiviral and antileukaemic sponge nucleosides by Bergmann and Feeney in the 1950’s (Bergmann and Feeney, 1950, 1951). Since then, thousands of sponge-derived bioactive compounds have been discovered (Faulkner 2000, 2001, 2002; MarinLit, 1999) increasing the importance of sponges as a high potential source of new drugs. Sponges have the potential to provide future drugs against important diseases, such as cancer, a range of viral diseases, and inflammations.

Over 18,000 marine natural products have been described. Over 30% of those products are derived from sponges. Of the antitumor natural product patent registrations in recent years, over 75% are from sponges¹,². The biological effects of newly discovered metabolites from sponges have been reported in hundreds of scientific papers. Although the molecular mode of action of most metabolites is still unclear, for a substantial number of compounds, the mechanisms by which they interfere with the pathogenesis of a wide range of diseases have been reported. This knowledge is one of the key factors necessary to transform bioactive compounds into medicines. Sponges produce a plethora of chemical compounds with widely varying carbon skeletons, which have been found to interfere with pathogenesis at many different points. The fact that a particular disease can be fought at different points increases the chance of developing selective drugs for specific targets.

A number of products have entered preclinical and clinical trials (Table I). Ara-A and Ara-C (derivatives of the sponge nucleosides discovered by Bergmann and Feeney) have advanced to the pharmaceutical market as antiviral and antileukemic agents, respectively (McConnell et al., 1994).

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^{1. [Faulkner DJ. Marine natural products. Nat Prod Rep. 2002;19:1–48. [PubMed]]↩}

^{2. [Sipkema D, Franssen MCR, Osinga R, Tramper J, Wijffels RH. Marine sponges as pharmacy. Mar Biotechnol. 2005;7:142–162. [PubMed]]↩}

Supply Challenge other companies face

Why aren't there more sponge-dervived drugs on the Market?

If it were only a matter of bioactivity, or having a unique pharmacological profile, hundreds of sponge-derived compounds could be expected to enter drug development in the coming decades. However, bioactivity alone does not determine whether or not a compound enters drug development in the pharmaceutical industry. Other factors such as establishment of a cost-effective source of large-scale supply, and ‘‘drugability’’ in a human model system are paramount in determining if a pharmaceutical company will prioritize a new natural product discovery for inclusion in its drug development pipeline. Expensive to produce, or scarcely available metabolites will only have a chance of entering drug development if they have truly unique pharmacological profiles including new mechanisms of action against a particular drug target or disease. Looking back on those sponge-derived compounds that have advanced to human clinical testing, it can be seen that all were found to be amenable to cost-effective chemical synthesis, thus solving the supply question early-on in the development continuum (Table I).

Wild harvest

Wild harvest of a prolific sponge that is the source of a desired metabolite would be an easy way to acquire a compound for preclinical studies and possibly even early-stage clinical trials. One only needs SCUBA diving equipment and a small boat for a first harvest, thus foregoing the need for investing in and setting-up complex culture systems for an organism that has been notoriously difficult to culture (Osinga et al., 1999).

However, while the wild harvest of marine invertebrates is considered plausible for pre-clinical studies, the collection of larger populations for clinical development and commercial production of an eventual clinical candidate is environmentally unsustainable due to insufficient or inaccessible natural populations and the typical low yields of bioactives¹,². Even so, halichondrin B pre-clinical development was started by harvesting more than one metric ton of the rare sponge Lyssodendoryx sp. from natural populations to afford only 310 mg of pure compound³. Also, bryostatin 1 progressed to Phase I clinical trials through the wild harvest of nearly 13 tons of the bryozoan Bugula neritina yielding 18 g of the anticancer candidate⁴.

The Villani Advantage

Sustainable Wild Harvest

Villani is the first company poised to commercialize a sustainable supply of valuable bioactive compounds derived from a wild harvest of aquatic sponge while protecting and maintaining the equilibrium of its ecosystem.

Villani is unique in the biotechnology industry in it's ability to provide highly effective natural bioactive compounds well-suited for pharmaceutical development, and supply the materials in commercial volume without depleting natural resources.

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