To date, there are nine therapeutic agents that derive from the marine environment—six anticancer, one antiviral, one for pain control, and one for hypertriglyceridemia. [© vilainecrevette/Fotolia.com]
Creatures from the sea have provided multiple new drug leads to treat human diseases. Of the total number of known phyla—which varies depending on the source—17 occur on land and 34 live in the ocean. Despite significant challenges inherent to natural product-derived drugs, several marine-derived agents have been approved, most as "first-in-class" drugs.
To date, there are nine therapeutic agents (six anticancer, one antiviral, one for pain control, and one for hypertriglyceridemia) that derive from the marine environment, according to William H. Gerwick, Ph.D., of Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego. These include the anticancer agent cytarabine, derived from a sponge, and ziconotide for severe pain based on a toxin derived from a marine snail.
Additionally, Dr. Gerwick noted, 13 agents with a marine origin are currently in clinical trials. Eleven are being tested for cancer treatment, one for cognition and schizophrenia, one for Alzheimer disease (along with cancer), and one for wound healing.
It's no surprise that most of the drugs derived from sea creatures usually originate as potent toxins designed to protect the creatures they come from. The big push in marine drug discovery has thus focused on cancer, Dr. Gerwick told Genetic Engineering & Biotechnology News (GEN): "Since we want to kill cancer cells we look for cytotoxins, and the marine environment is exceptionally rich in cytotoxins."
But, he added, "increasingly there is an understanding of the molecular basis of why cancer cells escape normal controls on proliferation. Thoughts are that other kinds of agents that don't kill the cell but take advantage of its biochemistry to redirect it into programmed cell death could be discovered." In terms of nontoxic drugs from the sea, Dr. Gerwick cited the success of Lovaza, a semisynthetic drug consisting of omega-3 fatty acids purified from fish, then synthetically converted to ethyl esters to allow for easier purifications. "It reduces drug lipids and has minimal if any side effects," Dr. Gerwick explained.
Synthesis and Development
While marine discovery scientists are "doing a good job and coming up with good leads and ideas," Dr. Gerwick points to challenges with fully developing those discoveries. "We advance the leads to the point where we can demonstrate bioactivity and maybe even some animal data, then we are confronted with crossing the so-called valley of death. It's very difficult and hard to navigate because of the risk, finances, and intellectual property issues."
Developing novel drugs from sea creatures takes tremendous resources. It took about 17 years to discover and develop the breast cancer drug Halaven, approved by the FDA in 2010, Ted Suh, Ph.D., senior director, lead identification at Eisai’s Andover, MA, site told GEN. Halaven is sanctioned for patients with metastatic breast cancer who have undergone treatment with two or more prior chemotherapy regimens.
Halaven acts as a microtubule dynamics inhibitor. It is a synthetic analog of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name suggests the almost insurmountable obstacles chemists faced in trying to produce a synthetic version: 11,15:18,21:24,28Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2’,3’:5,6]pyrano[4,3b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3methoxy-26-methyl-20,27- bis(methylene)(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt).
The size of the molecule along with complex ring structures and abundant stereochemistry add challenges to the synthesis of this molecule. Harvard professor Yoshito Kishi's landmark synthesis paved the way for Eisai's drug discovery efforts. "Following on professor Kishi's synthesis, we produced our own analog of the natural product, using a 62-step synthetic process," Dr. Suh explained. "That compares to just 10 steps or less for a typical drug."
As to why one just couldn't just squeeze the product out of the original sponge source, Dr. Suh pointed out, "We had to make kilogram quantities of an eventual drug, with no idea as to how to develop the product in such large amounts. Not only did our process research chemists, led by Dr. Frank Fang, reduce the number of synthetic steps, but they were also able to produce a route with many crystalline intermediates that resulted in increased drug purity and throughput with reduced cost."
Salinosporamide A is another potential drug candidate from the sea. It comes from the marine actinomycete Salinispora tropica and is currently in clinical trials as an anticancer agent. Discovered by William Fenical, Ph.D., and Paul Jensen, Ph.D., from Scripps Institution of Oceanography, an initial screening showed that organic extracts of cultured Salinispora strains had antibiotic and anticancer activities.
Eisai identified its drug candidate around 1998, according to Dr. Suh. "Our development capabilities grew along with the project, and our recent programs advance in less time." He also noted that finding the right way to run the clinical trials improved the time lines. The company remains committed to finding the next drug from the sea and looks to other natural product sources as well.
In the case of salinosporamide A, a 20S proteasome inhibitor, Dr. Jensen told GEN that no laboratory synthesis was required. "The microbe did the job for us," making enough of the compound in cell culture for clinical trails. "Although a number of synthetic routes have been achieved, they were not required for clinical development."
Drs. Fenical and Jensen discovered the molecule in 2003, and as Dr. Jensen commented, "It was a pretty fast-track molecule. Nereus Pharmaceuticals was fairly aggressive about getting the investigational new drug application (IND) filed." Nereus is currently testing its salinosporamide A-based compound, marizomib (NPI-0052), in phase 1 trials in multiple myeloma, lymphomas and leukemias. The company has another anticancer agent derived from a marine microbial source, Plinabulin, that is also at the phase 1 stage.
Dr. Jensen also credited Nereus with finding conditions under which the salt-requiring microbe could be grown to yield the highest levels of compound. "A big issue with finding a commercial fermentation facility was the need for high levels of salt in the medium, which causes significant corrosion," he said. "To get around this issue, Nereus did a lot of research and found low-salt fermentation formulas that supported good compound production."
Since that time, Dr. Jensen said, "We have identified what we believe is the genetic basis for the sea water requirement. Surprisingly a key factor appears to be a gene that was lost by Salinispora. These bacteria shared a common ancestor with actinomyces that lived on land and were equipped with an osmotic stress gene that allowed them to tolerate rapid changes in osmolarity. "Millions of years ago, as the Salinispora group of organisms became adapted to life in the ocean, they appear to have lost the need for this gene because ocean salinity remains fairly consistent."
Getting More from the Sea
"We continue to study these organisms to find new compounds that hit other targets," Dr. Jensen commented. "In collaboration with my colleague Dr. Brad Moore, we are now mining the genome sequences of Salinispora strains to predict which strains have the greatest chances of producing interesting new natural products."
Dr. Suh of Eisai echoed a similar sentiment. "Marine sources are important to us because of our commitment to the cancer space and because we have many partnerships that help us find specimens. We don’t have the resources or expertise to go out into the field to find and characterize specimens. Once we have a structure and biological activity, we can translate structures into entire programs."
Eisai works closely with the International Cooperative Biodiversity Groups (ICBG), an NIH sponsored program that puts academic researchers together with industrial partners and host countries recognized as "biodiversity hotspots." Dr. Suh said that Eisai currently participates in programs in Madagascar, Panama and Costa Rica and that they are looking to expand into the Philippines. While Eisai focuses on cancer, the company routinely puts its compounds and extracts through assays for neurodegenerative diseases such as Parkinson and Alzheimer diseases and for some autoimmune disorders like lupus and RA, Dr. Suh added.
Prompted by the need to replenish drug pipelines, pharma companies may increasingly turn to sea-borne organisms. These creatures will undoubtedly continue to yield an array of cytotoxic agents for cancer as well as interesting compounds for other human diseases.
Patricia F. Dimond
Genetic Engineering & Biotechnology News