Anti-malarial Compounds from Marine Natural Products

Application

Compounds derived from marine and natural products have potent anti-malarial activity and include cembranoid-type diterpenes, microsclerodermins, dercitamides, and bis-indoles. These agents can be used to treat or prevent malarial infection.

Problem

Malaria, an infectious disease caused by Plasmodium parasite transmission from mosquitoes, is one of the most severe public health problems worldwide. It is the leading cause of death and disease in many developing countries, with young children and pregnant women most commonly affected. Over 3.4 billion people (half of the world’s population) live in areas at risk for malaria transmission (106 countries and territories). An estimated 207 million people contracted malaria in 2012, resulting in 627,000 reported deaths of which 90% were in Sub-Saharan Africa and 77% were among children under 5. It imposes a substantial economic burden to individuals and governments, with costs estimated at more than $12 billion per year, not including the total loss in economic growth. As a result of the emergence of a combination of new interventions including reliable diagnostic tests and effective drugs, the number of new cases has declined 25% with a 42% reduction in deaths. However, current tools and treatments are insufficient to eliminate malaria, as more drug resistant strains have developed and continued to spread and a vaccine is still unavailable. Therefore, there is a significant need for new drugs and strategies to treat and prevent malarial infection.

Technology

The inventors have isolated four novel classes of anti-malarial compounds from marine and natural products that have potent, and selective anti-malarial activity and include cembranoid-type diterpenes, microsclerodermins, dercitamides, and bis-indoles. Since these compounds have unique structures, they likely act upon novel cellular targets and may alleviate the drug resistance problem of current treatments. This technology proposes methods for treating and/or preventing malarial infection using these new agents. The compositions can be administered individually or in combination with at least one other agent including a stabilizing compound or other therapeutic agent currently used for the treatment/prevention of malaria.

Competitive Advantage

Living organisms such as marine life are a recognized source of potentially bioactive molecules, which a commonly more effective than those obtained through combinatorial synthetic chemistry. Although synthetic libraries are straightforward to assemble, there are a limited number of synthetic reactions and structurally diverse building blocks, implicating a lack of structurally diversity and exploration of the biological space. Marine natural products are also enzymatically engineered and biologically validated, representing a higher quality product. Not surprisingly, the most significant recent advancements in malaria have been made through natural leads. This technology is a product derived from natural marine products and shows highly selective, potent activity against chloroquine resistant strains of P. falciparum. The inventors anticipate the technology to act on novel cellular targets, which is highly advantageous since resistant malaria strains are becoming more prevalent and continue to multiply despite being treated with anti-malarial compounds. It is also expected that the next significant advancement in anti-malarial drugs will not be reached through the discovery of a single, potent compound, but rather through the introduction of an innovative drug to be used in a combined therapy, preferably composed of molecules acting at different stages of the microorganisms’ life cycle. The proposed technology is highly advantageous since its activity can be retained and enhanced through combinatorial therapy and its stability can be increased with a stabilizing compound.

Opportunity

Due to widespread resistance to commonly used anti-malarial oral drugs such as chloroquine and anti-folates, in 2006, an endoperoxide sesquiterpene from Artemisia annua (Chinese herbal remedy) called artemisinin, became the frontline therapy for treatment of malaria. Artemisinin and its derivatives are currently the only viable, cheap options for treatment. However, in 2014, the WHO declared rapid withdrawal of artemisinin monotherapy due to the emergence and spread of artemisinin-resistant strains. The continuous appearance of drug-resistant P. falciparum strains has made the chemotherapeutic management of malaria increasingly problematic in virtually all malaria-plagued regions of the world. Compounded by the absence of a vaccine for protection, this recent epidemic of resistance has underscored the importance of developing new drugs and new drug targets to treat the disease. As a result of artemisinin resistance, an artemisinin combination therapy (ACT) is now the standard of treatment worldwide. Intense efforts are currently being made to extend the life of existing drugs while major drug discovery initiatives are underway. The current technology certainly has a well-defined place in the market as a novel treatment with novel targets, which can be effectively developed into a combination therapy.

Stage of Development

• Screening, isolation, and identification of marine compounds with anti-malarial activity • Anti-plasmoidal activity tested in P. falciparum choloroquine-resistant Dd2 cells
• Cytotoxicity tested in NIH 3T3 cells (mouse embryonic fibroblasts) to verify selectivity • Pharmaceutical compositions comprising one or more anti-malarial agents have been
identified (with and without carriers) • Strategy for determining the effective therapeutic dose in place

Patent Status

A patent has been issued for the anti-malarial compounds technology. The University of Central Florida and Florida Atlantic University are looking for a partner for further development and commercialization of this technology through a license. U.S. Patent Publication: 20140200226A1 Publication Date: July 17, 2014

Researchers

Dr. Debopam Chakrabarti, Ph.D., is a Professor at Central Florida’s Burnett School of Biomedical Sciences. With 25 years of experience in molecular parasitology, target validation, and anti-infective drug discovery, he has authored over 86 peer-reviewed publications. Amy Wright, Ph.D. (UC, Riverside) has been working in the field of Marine Natural Products Chemistry for over 24 years. Her primary research interests focus on the purification and structure identification of naturally occurring compounds, which may have utility in treating cancer. Much of the research focuses on the investigation of deep-sea invertebrates collected using the Johnson-Sea-Link human- occupied submersibles. She has over 150 Peer Reviewed publications. Her past partnerships with large and small biotechs, Sanford Burnham, Moffitt Cancer Center, with funding from NIAID, MIGMS, MCCAM, & NOAA. Through her research, she has access to a vast (5,000+) natural marine compounds library http://dorsrv1.fau.edu/CEBMB/Libraries.aspx.

Field

Medical/molecular parasitology, infectious disease, drug discovery