identify a marine organism and report what type of molecule it can make.

Anonymous
timer Asked: Oct 24th, 2018
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Question description

In this exercise I want you to identify a marine organism and report what type of molecule it can make and what the 1. activity of the compound in the natural environment is ( example: fend off prey or attract prey, to name a few) and 2. how its activity can be used as a drug or therapeutic.

Please write a 500 word write up on the topic and include citations (not included in 500 word length)

Antimicrobial Drug Discovery from Sea to Space Aubrie O’Rourke Despite the combined screening efforts of synthetic chemical libraries around the world, antiviral drug approvals continue to be elusive either for a lack of chemical diversity in the material screened or for a lack of diversity in assayed targets. In the period of 2008 to 2013, Hepatitis C Virus (HCV) was the only virus with a compound in clinical trials- a derivative of the natural product, cyclosporine A [1]. This is in stark contrast to the 71 natural product derivatives targeting cancers in clinical trials during the same period [1]. Historically, viruses with an association to cancer have been well studied. It was upon the advent of a lentivirus in 1983 with a less oncogenic, yet chronic manifestation, known as the human immunodeficiency virus (HIV), that the characterization of “complex” retrovirus advanced upon the previous research efforts into the “simple” tumor-forming retroviruses. Immediately, the National Cancer Institute recognized the need for an anti-AIDS division and incorporated antiviral screening into their program. With this necessary momentum, the FDA approved the first reverse transcriptase inhibitor, azidothymindine (AZT), in 1987[2]. Since then inhibitors targeting the viral protease and reverse transcriptase, among other virally encoded proteins, have been approved. However, there remains a demand for new drugs as new mutations arise because of the error prone HIV reverse transcriptase and quick replication rate, thus causing an arms race of sorts. The best weapon so far has been the Highly Active Antiretroviral Therapy (HAART) where combination therapy is used to reduce viral load. However, latent reservoirs containing drug-resistant variants of the virus exist [3] and necessitate the search for new antiretrovirals. Natural products offer chemical scaffolds that occupy a drug-like chemical space from which novel therapeutics can be generated. This area of study continues to produce new leads in the academic setting as we tap into the natural reserves offered by less accessible organisms, such as those found in the marine environment. In a survey of marine natural products, it was found that for most years, anticancer activity has dominated the bioactivity spectrum. However, years in which bioactivity reports exceed the 25% average were years that included screens beyond cancer inhibition and included a diversity of antibacterial, antifungal, and antiviral screens [4].This suggests many bioactivities remain to be discovered for existing compounds. Marine organisms are a source for new discovery as they are under constant bombardment by marine microorganisms such as marine bacteria, which exist in the ocean at an abundance of approximately 106 cells/ml [5]. Many of these bacteria have found their ecological niche within sponges and generate secondary metabolites in defense against the ambient bacterial load. This has spurred the search for antibiotics from marine invertebrates. However, it is estimated that the abundance of marine viruses is an order of magnitude higher than that of bacteria and archaea, with approximately 15 x 106/ml in the water column comprised of 1030 viruses in total [6]. It is then not hard to imagine that sessile marine invertebrates, such as sponges, produce secondary metabolites that have an evolutionarily selected ability to inhibit viruses. Furthermore, there is additional evidence to suggest that retroviruses, ancestors to HIV-1, originated in the ocean 450 million years ago [7]. The search for marine derived antiviral pharmacophores is not without precedent as the first antiretroviral medicine, AZT, approved for the treatment of HIV was inspired by a natural product produced by a sponge and is known as Ara-A [8]. It became a working hypothesis that sponges endemic to the highly isolated and ancient Red Sea should harbor metabolites which have protected sponges and their symbionts from a multitude of viruses over millions of years of coevolution. To test this hypothesis, we harvested and extracted small cuts from a number of Red Sea sponges in order to screen the extracts against the HIV-1 virus in both a cell-based and biochemical assay. As a result, a promising hit in the cell-based HIV-1 assay was discovered from Stylissa carteri. The extract exhibited minimal cytotoxicity and an undocumented anti-HIV-1 activity. The S. carteri extract was further examined using the analytical chemistry technique of liquid chromatography-mass spectrometry (LC-MS). Here it was found that the compounds present in the greatest relative abundance were three known alkaloids that had been chemically synthesized. Thus, we knew the exact chemical structures of the natural products and it became possible to bioinformatically analyze their similarity to the structures of known HIV-1 inhibitors. Interestingly, this family of alkaloids was most chemically similar to the reverse transcriptase family of inhibitors. To test the accuracy of the prediction, the procured compounds were screened on an HIV-1 reverse transcriptase biochemical assay and here a significant inhibition of the reverse transcriptase was observed for one compound. This compound was also found to be less cytotoxic than the original extract placing it within range to be followed up as a potential therapeutic. Shockingly, this well-characterized compound had been successfully synthesized yet had never undergone a thorough screening against one of the most significant viruses of our lifetime, HIV-1. This work highlights the importance of screening natural products against novel and known targets in order to identify novel therapeutics. My postdoctoral research continues along these lines. In my most current work, as part of a postdoctoral fellowship from NASA, I will investigate a Burkholderia species isolated from the International Space Station (ISS). Burkholderia is commonly found in soils that also harbor the fungal species Aspergillus. As a result of their coevolution, certain species of Burkholderia produce a number of antifungal compounds [9,10]. Aspergillus has also been cultured from the air and surfaces of the ISS [11]. Burkholderia metabolites could be altered on account of space adaptation and provide a source of antifungals, another class of compounds underrepresented in clinical trials, which could potentially treat terrestrial and space-adapted Aspergillus infections. Natural product drug discovery offers the opportunity to mine for novel therapeutic scaffolds from any habitat imaginable, from sea to space, in order to target the molecular mechanisms of infectious disease. 1. Butler MS, Robertson A a B, Cooper M a. Natural product and natural product derived drugs in clinical trials. Nat Prod Rep. Royal Society of Chemistry; 2014;31: 1612–1661. doi:10.1039/c4np00064a 2. Broder S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. NIH Public Access; 2010;85: 1–18. doi:10.1016/j.antiviral.2009.10.002 3. Chun TW, Fauci a S. Latent reservoirs of HIV: obstacles to the eradication of virus. Proc Natl Acad Sci U S A. 1999;96: 10958–10961. doi:10.1073/pnas.96.20.10958 4. Hu Y, Chen J, Hu G, Yu J, Zhu X, Lin Y, et al. Statistical Research on the Bioactivity of New Marine Natural Products Discovered during the 28 Years from 1985 to 2012. Mar Drugs. 2015;13: 202– 221. doi:10.3390/md13010202 5. Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the unseen majority. Proc Natl Acad Sci U S A. 1998;95: 6578–83. doi:10.1073/pnas.95.12.6578 6. Breitbart M. Marine Viruses: Truth or Dare. Ann Rev Mar Sci. 2012;4: 425–448. doi:10.1146/annurev-marine-120709-142805 7. Aiewsakun P, Katzourakis A. Marine origin of retroviruses in the early Palaeozoic Era. Nat Commun. Nature Publishing Group; 2017;8: 13954. doi:10.1038/ncomms13954 8. Hassan SS ul, Shaikh AL. Marine actinobacteria as a drug treasure house. Biomed Pharmacother. 2017;87: 46–57. doi:10.1016/j.biopha.2016.12.086 9. El-Banna N, Winkelmann G. Pyrrolnitrin from Burkholderia cepacia: Antibiotic activity against fungi and novel activities against streptomycetes. J Appl Microbiol. 1998;85: 69–78. doi:10.1046/j.1365-2672.1998.00473.x 10. Lin Z, Falkinham JO, Tawfik KA, Jeffs P, Bray B, Dubay G, et al. Burkholdines from Burkholderia ambifaria: Antifungal agents and possible virulence factors. J Nat Prod. 2012;75: 1518–1523. doi:10.1021/np300108u 11. Knox BP. Characterization of Aspergillus fumigatus Isolates from Air and Surfaces of the International Space Station | mSphere. In: American Society for Microbiology [Internet]. 2017 [cited 10 Jul 2017]. Available: http://msphere.asm.org/content/1/5/e00227-16

Tutor Answer

henryprofessor
School: UT Austin

Attached.

Ara-A from Caribbean Sponges
Thesis statement: The spongouridine Ara-A is an important chemical in the survival of
the Tethya crypta are also commonly called the Caribbean sponges and also useful in treating
HIV in humans.
I.
II.

Introduction
Description of Ara-A and use in sponges

III.

Ara-A in HIV treatment

IV.

Conclusion


Running head: ARA-A FROM CARIBBEAN SPONGES

Ara-A from Caribbean Sponges
Name
Institution

1

ARA-A FROM CARIBBEAN SPONGES

2

Ara-A from Caribbean Sponges
Sponges are among the most abundant organisms in the marine environment. They are
also among the oldest multicellular organisms in the world. The ability of the sponges to survive
in the water, just like many other marine organisms is aided by the secondary metabolites that
they produce. Secondary metabolites are chemic...

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Anonymous
Top quality work from this guy! I'll be back!

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