Marine Natural Products in Clinical Use

Abstract

Marine natural products are potent and promising sources of drugs among other natural products of plant, animal, and microbial origin. To date, 20 drugs from marine sources are in clinical use. Most approved marine compounds are antineoplastic, but some are also used for chronic neuropathic pain, for heparin overdosage, as haptens and vaccine carriers, and for omega-3 fatty-acid supplementation in the diet. Marine drugs have diverse structural characteristics and mechanisms of action. A considerable increase in the number of marine drugs approved for clinical use has occurred in the past few decades, which may be attributed to increasing research on marine compounds in laboratories across the world. In the present manuscript, we comprehensively studied all marine drugs that have been successfully used in the clinic. Researchers and clinicians are hopeful to discover many more drugs, as a large number of marine natural compounds are being investigated in preclinical and clinical studies.

Keywords: DNA alkylating agent; drug conjugated with an antibody; fish oil; marine drugs; marine natural products; microtubule inhibitors; peptides or proteins; spongonucleosides.

Figure 1

The structures of thymidine and other arabinosides.

Figure 2

Mechanism of resistance to ara-C in normal cells and cytotoxicity in lymphoma. Compared to normal cells, lymphoma cells show more influx and less efflux of ara-C. A series of phosphorylation events by deoxycytidine kinase (dCK), followed by nucleoside monophosphate kinase (NMPK) and nucleoside diphosphate kinase (NDPK), occurs that convert ara-C to bioactive ara-CTP.

Figure 3

Histochrome structure.

Figure 4

Structures of the naturally occurring marine compound (A) halichondrin B and its synthetic analog (B) eribulin mesylate.

Figure 5

Schematic molecular representations of (A) trabectedin and (B) lurbinectedin.

Figure 6

A representative illustration of the mechanism of trabectedin action. (A) The bilayer shows the nucleus, DNA strands are shown in red and blue stranded, and the inverted triangle in the minor groove represents trabectedin binding. (A1) DNA damage caused by trabectedin. (A2) The inhibition of transcription elongation by the inhibition of transcription factors and other related enzymes. (A3) The interference of trabectedin with the DNA repair machinery. (B) The extracellular matrix and the tumor microenvironment. TAMs and monocytes undergo cell death following inhibition by trabectedin, and trabectedin is shown in 2D in black stick representation.

Figure 7

Sketch of an ADC. The antibody is connected to an attachment group that is further connected to an enzyme cleavage site. The drug is bonded to the cleavage site. Brentuximab vedotin differs from polatuzumab vedotin.

Figure 8

Schematic representation of the major mechanisms of action of brentuximab and polatuzumab: (A) binding of the ADC to the cell surface antigen (CD30/CD79b); (B) internalization of the ADC–cell surface antigen complex into the cell; (C) transportation of the ADC to the lysosome; (D) release of MMAE by lysosomal enzyme hydrolysis and the inhibition of tubule polymerization, resulting in apoptosis and cell death. The elimination of MMAE is mostly through CYP3A4/5 metabolic pathway and excretion via bile and feces. The half-life of MMAE is much shorter (~2.5 h) than that of the MMAE–antibody conjugate, which is 2.5–3 days [155].

Figure 9

Molecules of the didemnin class. (A) General structure of didemnin, where “R” represents different substitutions in various didemnin members. (B) Simplified linear representation of a general didemnin. (C) Plitidepsin is similar to didemnin B, with a difference only in the terminal lactate that is oxidized to pyruvate. Short representations of residues: MeLeu—methyl leucine, Thr—threonine, Sta—statin, Hip—hydroxyisovalerylpropionic acid, Leu—leucine, Pro—proline, Me2Tyr—dimethyl tyrosine, Lac—lactate, Pyr—pyruvate, p-Glu—cyclic glutamate, and Gln—glutamine.

Figure 10

Mechanism of action of plitidepsin. Plitidepsin binds with eEF1A2 and blocks proteasomal aggresome degradation of misfolded proteins.

Figure 11

(A) Linear model of ziconotide with cross-linking of disulfide bonds. (B) A 3D knotted model of ziconotide. (C) Schematic diagram of ziconotide blocking the N-type calcium channel.

Figure 12

Cationic protamine sulfate reverses the anticoagulant effect of heparin by forming an ionic complex with heparin, which facilitates strong binding of factor Xa and weak binding of antithrombin and restores the natural coagulation process.

Figure 13

(A) KLH barrel-shaped representation drawn using cryo-electron microscopy 3D coordinates (PDB ID 4BED). (B) KLH as a hapten conjugate. (C) KLH as a vaccine carrier.

Figure 14

Omega-3 fatty acids and their derivatives.

Figure 15

Mechanism via which omega-3 fatty acids lower triglycerides and the conversion of very-low-density lipoprotein (VLDL) into low-density lipoprotein (LDL).

Figure 16

Cumulative number of marine drugs available on the market at the end of consecutive decades from 1970 to 2020.