MARINE NATURAL PRODUCTS AS ANALGESIC AGENTS
Ziconotide was the first analgesic drug of marine origin to obtain approval from die U.S Food and Drug Administration (USFDA) to treat the pain. The analgesic property of ziconotide is found to have role in blocking of N-type calcium channels on the primary nociceptive nerves of the spinal cord in animal studies [274]. At the end of 2004 after twenty years of research on die toxins from predatory molluscan gasfropods of genus Conus, the toxin got approval for making and clinical use in die USA. After few months, its production was started in Europe under the commercial name “prialt.” Elan Pharmaceuticals launched Prialt® (Ziconotide) as a remedy for chronic pain due to its noteworthy anti-nociceptive action even in patients not responsive to morphine.
Ziconotide is a peptide consisting of 25-amino acid derived from the co-conotoxin, a toxin from cone snail (Conus magus) found in tropical sea, [187]. The snails produce conotoxin for fish hunting to immobilize the prey by acting on the neuromuscular system [213]. In patients, co-conotoxin acts by blocking the N-type voltage-sensitive calcium channels and inhibiting the neurotransmitters release thereby interrupting the nerve signal conduction leading to pain relief [212]. Since the large-scale production is limited due to the lack of enough biological specimens; and ziconotide was produced by peptide synthesis [5, 148].
Conotoxin МЛТ1А, being a natural toxin, was of top priority as a prospective drug compared to their synthetic derivatives. The co-conotoxin is a linear peptide consisting of 25 amino acid residues with six-cysteine residues forming three disulfide bridges [52, 214]. Neurex (branch Elan Pharmaceuticals) company carried out clinical investigations of synthetic co-conotoxin [307]. These investigations showed that ziconotide does not have hallucinogenic effects and does not cause addiction, as in morphine [188]. Many conotoxins are still in different phases of investigation as analgesic drugs [114]. Tetrodotoxin (TTX) 24 (a guanidine alkaloid isolated from fish, algae, and bacteria) was found to block the voltage-dependent sodium channels [325] and has shown analgesic property in cancer patients [123, 125].
MARINE NATURAL PRODUCTS AGAINST CARDIO VASCULAR DISEASES
The risk factors related to CVD and atherosclerosis are the quantity and type of fatty acids (FAs) in our daily diet [177]. According to the World Health Organization (WHO), CVD, and stroke will remain the leading causes of death and about 23.6 million people will die due to CVD in 2030 [316].
Significant discoveries have resulted in drugs from marine organisms against CVD [279]. Activation of thrombin receptor plays a key role in arterial thrombosis and atherosclerosis [45]. Atherosclerosis begins with damage of endothelium and ensuing deposition of fats, cholesterol platelets, cellular waste products, calcium, and other substances on the arterial wall [272]. Studies show that halichlorine from sponge (Halichondria okadai) inhibits the vascular cell adhesion molecule 1 expression [162]. Two polysaccharides isolated from sea cucumber (a fucosylated chondroitin sulfate and a sulfated fucan) showed anti-thrombic activity [143,199].
MARINE NATURAL PRODUCTS AGAINST HYPERTENSION
Hypertension or high blood pressure is a chronic medical condition resulting in elevated blood pressure in the arteries [72]. Thus, ACE inhibitors can be used for the treatment of hypertension; and there is a need for increased demand for natural or food-derived inhibitors [303] due to the adverse side effects [13]. The peptides showed IC50 values 3.09 and 4.22 pM, respectively for the anti-hypertensive activities [205]. An anti-angiotensin I converting enzyme (ACE) peptide (Ala-His-Ile-Ile-Ile, with MW: 565.3Da) was isolated from Styela clava. The induction of vasorelaxation in the rat aortas was observed with the isolated fractions and the peptide [153].
However, due to complex nature of constituents and the amino acid in seaweed hydrolysates, sequencing of bioactive peptides in ACE-active hydrolysates is rarely determined. Antihypertensive properties of peptides from macroalgae have also been shown in humans. Diet with a tridecapep- tide obtained from Palmaria palmata after papain digestion has shown to be active against renin [92] and could potentially reduce the systolic blood pressure of about 33 nmrHg in spontaneously-hypertensive rats [91]. hr addition, many di- and tetrapeptides from Undaria pinnafita have been characterized by Suetsuna and coworkers [285, 286]. Among them, diet supplementation with dipetides and the tetrapeptides significantly lowered the blood pressure in spontaneously hypertensive rats [285].
MARINE NATURAL PRODUCTS AGAINST HIV
By early 2003, screening of drugs against HIV from marine sources established more than 150 highly active marine metabolites [105, 299]. Peptides from some marine invertebrates are especially good sources of antiviral substances. Peptides are composed of 17-18 amino-acid residues [193, 198]. Four new cyclic depsipeptides (termed mirabamides А, В, C, D) have been isolated from the sponge SiJiquariaspongia mirabilis with antiviral properties [227]. Anti- HR" activity of Mirabamide A, C, and D was performed using neutralization and fusion assays. The IC50 values of Mirabamide A was between 40-140 nM, and for Mirabamide C, ICJ0 value ranged between 140 nM-1.3 pM and 190 nM and 3.9 pM for Mirabamide D, showing that these peptides can prevent HR- entry in the early stages [238]. Another cyclodepsipeptide homophymine A, isolated from the marine sponge Homophymia sp„ exhibited cyto-protective activity against HR" infestation (ICJ0 of 75 nM) with MTT assay [327].
It was found to inhibit protein tyrosine phosphatase IB. Another new C22 furano-terpene (dehydrofurodendin) isolated from the sponge (Madagascan Lendeiifeldia) was found to be active against HIV-1 RT with an ICJ0 value of 3.2-5.6 pM [50]. Bioassay-guided fractionation of extracts of the Palauan ascidian (Didemnum guttatimi) led to the isolation of a sulfated serinolipid, cyclodidemniserinol trisulfate, as an inhibitor of HIV-1 integrase [191].
Metabolites fr om sponges (such as avarol, avarone, ilimaquinone, and several phloroglucinols) exhibited anti-HIV activity [299, 324]. Avarol inhibited HIV almost completely by blocking the synthesis of the natural UAG suppressor glutamine transfer tRNA, synthesis of which is upregulated after viral infection and is important for the synthesis of a viral protease, which is necessary for viral proliferation [200]. A novel and active sulfated sterol, Clathsterol from the sponge Clatliria sp., inhibited HIV-1 RT at a concentration of 10 ,uM [249].
Lamellarin, an alkaloid, showed anti-HR" activity by inhibiting the activity of strands transfer and integrase terminal cleavage [239]. Lamellarin was earlier purified from the mollusk Lamellaria and later was also found in Didemnid ascidiaiis [6]. Neamphamide A, a new HIV-inhibitory depsipeptide from the Papua New Guinea marine sponge Neamphius huxleyi, repressed cytopathic effect (CPE) of HIV-1 infection [210]. Fan and his coworkers in 2010 reported some sulphated alkaloids as anti-HIV agents, named as bacu- liferins A-О from the Chinese marine sponge lotrochota baculifera [82].
