Immunomodulatory Compounds from the Sea: From the Origins to a Modern Marine Pharmacopoeia

Abstract

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.

Keywords: autoimmunity; bioprospecting; deep sea; drug discovery; genetic engineering; immunomodulation; inflammation; rheumatoid arthritis; synthetic biology; systemic sclerosis.

Figure 2

Chemical structures of recently identified immunomodulatory and anti-inflammatory compounds from deep-sea organisms described in Table 1. (1) 7,13-epoxyl-macrolactin A from Bacillus subtilis B5; (2) cyclopenol from Aspergillus sp. [237]; (3–9) hepialiamide, polyketide hepialide, 5′-O-Acetyladenosine, uridine, ergosterol, walterolactone A, and (4R, 5S)-5-hydroxyhexan-4-olide from Samsoniella hepiali W7; (10) myrothecol from Myrothecium sp. [239]; (11) eremophilane from Acremonium sp. and Eutypella sp. [240,241] (12–14) oxaline, isorhodoptilometrin, and 5-hydroxy-7-(2′-hydroxypropyl)-2-methyl-chromone from Penicillium oxalicum [242]; (15) chrysamide from Penicillium chrysogenum [243]; and (16) phenazostatin from Cystobasidium laryngis [244].

Figure 1

Marine pharmacology has come a long way, from superstitious practices to present-day high-throughput drug discovery pipelines. During the last three decades, the bioprospecting of marine environments has identified hundreds of lead compounds with potential applications in the clinical management of chronic inflammatory diseases and cancer. Historically, the East and West established their own corpuses of marine materia medica. During the last Chinese Imperial Dynasty of the Qing (1644–1911), European missionaries visited and established themselves in China, introducing the Christian faith and other Western cultural elements, including cartography. At the court of the Qing Emperor Shengzu, the Flemish Jesuit and astronomer Ferdinand Verbiest (1623–1688) published the Kunyu Quantu (坤舆全图, Full Map of the World) in 1674, one of several Chinese world maps produced in that era. Geography offered a glimpse into the outer world, attracting the attention of the traditionally self-centered and self-isolated Chinese civilization towards Western science. In the modern era, these two distant cultural worlds began a cross-fertilization of knowledge and, today, they together contribute to advancing the applications of marine resources in human health. Reproduced from [107].

Figure 3

Antifibrotic activity of EchA in SSc model. EchA reduces skin cell infiltration (M1 and M2 macrophages) and myofibroblast activation, ameliorating skin thickness. Cytokines (IL), cluster of differentiation (CD), reactive oxygen species (ROS), protein-coupled receptor signaling pathway (CCL), transforming growth factor (TGF-β), platelet-derived growth factor receptors (PDGF-Rs), fibroblast growth factor receptor (FGFRs), and Echinochrome A (EchA). Figure created with Biorender (accessed on 12 June 2024), based on [279].

Figure 4

Immune surveillance and immunotherapy with immune checkpoint inhibitors. Illustration of in vitro EPS immunostimulant effect on monocyte-derived macrophages. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), antigen-presenting cell (APC), cytotoxic T-Lymphocyte antigen 4 (CTLA4), T cell receptor (TCR), cytokines (IL), cluster of differentiation (CD), human monocytic cell line (THP-1), tumor necrosis factor (TNF), phorbol 12-myristate13-acetate (PMA), and extracellular polysaccharides s(EPS). Figure created with Biorender (accessed on 12 June 2024), based on [233].