Marine Arthropods: Comparison
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Peptide therapeutics play a key role in the development of new medical treatments. The traditional focus on endogenous peptides has shifted from first discovering other natural sources of these molecules, to later synthesizing those with unique bioactivities. Marine arthropods do not have an adaptive immune system, and therefore, they depend on the innate immune system to eliminate pathogens. Antimicrobial peptides (AMPs) with unique characteristics are a pivotal part of the defense systems of these organisms.

  • antimicrobial peptides
  • AMP
  • crustaceans

1. Introduction

Bioactive peptides have a broad spectrum of biological activities; from these, their immune signaling role stands out, due to their high selectivity and specificity for extracellular and intracellular target receptors. They are found in all living systems and play a decisive role in several physiological functions [1]. Given their vast variability and bioactive properties, peptides are considered to be pharmacologically ideal, in terms of safety, tolerability, and efficacy profiles, for the design of novel therapeutics for humans [2], thus increasing the wide family of traditional bioactive natural products from diverse sources such as plants, animals, and even bacteria [3,4][3][4]. Regulatory agencies have already approved around 100 pharmaceuticals in which a peptide serves as the active pharmaceutical ingredient (API) [5,6][5][6]. Of note, although cancer was traditionally the most important target for peptide-based drugs, recent years have witnessed the presence of bioactive peptides in practically all targets, with a special incidence in metabolic diseases and in radiopharmaceuticals [7].
Bioactive peptides can be isolated from natural sources. Such is the case of insulin, adrenocorticotropic hormone (ACTH), and calcitonin (canine or bovine pancreas, bovine or porcine pituitary glands, and salmon ultimobranchial gland), or they can be chemically synthesized or produced via fermentation [8]. In that regard, venoms from a wide range of animals, including cnidarians, echinoderms, mollusks, arthropods, and vertebrates, are now recognized sources of bioactive peptides for new potential therapeutics. In most cases, the isolation of peptides from natural sources is associated with the drug discovery process, which seeks to identify peptide sequences with the potential to become peptide drugs that can be produced synthetically or through genetic engineering [9]. Given their lack of stability in plasma and their poor ability to be transported through cell membranes as a result of the hydrophilicity inherent to their structures, native peptides face some limitations to becoming drugs. In this regard, the field of peptide chemistry is critical for the development of stable, active, and specific sequences of peptides with potential therapeutic uses. To this end, current strategies include the use of D-enantiomers, the modification of side chain length, the use of N-methylation or bulky residues, terminal capping, and cyclization to overcome protease degradation.
In addition, peptides are considered suitable templates for introducing chemical modifications, resulting in peptide mimetics that have also been approved by the corresponding regulatory agencies. Heterologous peptide discovery through synthetic library screening has resulted in the approval of only a few peptide drugs for clinical use. However, peptide analogues show improved properties over native peptides and they are the major chemical basis for new peptide drugs. In conclusion, advances in peptide chemistry and synthesis, and in drug delivery systems have brought about the success of peptide therapeutics and their conjugates.
Thus, the use of peptides with biological activity in therapeutics has growth significantly [10,11,12,13,14,15][10][11][12][13][14][15]. In this context, marine organisms are a major source of such molecules because their immune systems exert powerful action against several viral and bacterial diseases [16,17,18][16][17][18]. In this context, antimicrobial peptides (AMPs) play a key role in strengthening the immune systems of these creatures. The relevance of bioactive peptides is reflected in several reviews on AMPs in mammals [19], amphibians [20], fishes [21], plants [22], insects [23], echinoderms [24], marine arthropods [16[16][25][26],25,26], and penaeid shrimps [27,28][27][28]. Remarkable research has been conducted in this area [29]; therefore, our reviewesearchers emphasizes the synthetic chemistry of AMPs and their tentative medicinal applications. WeResearchers describe recent advances regarding the molecular analysis of crustacean AMPs, concentrating on the antimicrobial mechanisms of these molecules against most pathogens in aquatic arthropods. These peptides not only serve to protect the organism against microbes (including Gram-positive and Gram-negative bacteria, yeast, and fungi) but also have antitumoral effects and mitogenic and immunoregulatory activity [30].
The immune response of crustaceans and chelicerates (Ecdysozoa, Arthropoda) is regulated on the external cuticle and the innate immune system, involving humoral and cellular effectors. Hemocytes are essential for the cellular immunity of these organisms, as they are involved in the storage and release of several defense molecules, including AMPs. Around 10% of animal-derived AMPs are from crustaceans, most of them (14 out of 15 families) having been identified in the decapod order (crabs, lobsters, crayfish, and several shrimp species) [31]. In marine crustaceans, the internal defenses rely on cellular and humoral responses (including pattern-recognition receptors/proteins, the production of reactive oxygen species, enzymatic cascades, clotting proteins, and AMPs) of the innate immune system that are mediated by blood cells or hemocytes [32]. The broad spectrum of biological activity shown by AMPs is a result of the wide variability of the subgroups and isoforms in a few families of these bioactive molecules. Indeed, current knowledge with regard to AMPs derived from marine crustaceans refers mostly to Decapoda, and thus does not represent the high diversity of sources [31,33][31][33]. AMPs are defined as cationic, amphipathic, and single gene-encoded molecules (also expanded to anionic and multigene-encoded). Their structure predisposes them toward interaction with the bacterial membrane, and they are therefore a promising source of next-generation antibiotics.
In terms of amino acid composition, AMPs are classified into four groups: single-domain linear α-helical AMPs (e.g., armadillidin and homarin); single-domain AMPs containing Cys residues engaged in disulfide bonds (e.g., defensins, scygonadins, and anti-lipopolysaccharide factors (Alefs)); multi-domain or chimeric AMPs (e.g., penaedins, crustins, hyastatin, etc.); and unconventional AMPs, including multifunctional proteins and protein-derived fragments (e.g., histones and hemocyanin) [31]. Most AMPs display a broad spectrum of antimicrobial properties against bacteria, viruses, fungi, and protozoa. Penaedins and ALFs have potential uses in therapeutics due to a lower risk of resistance, a low toxicity, and potential immune modulator function. A major advantage of AMPs from marine crustaceans is their stability in the gastrointestinal tract environment.

2. Bioactive Peptides in the Subphylum Crustacea

Diversity and Distribution

AMPs are ubiquitous defense molecules found in all life forms; unicellular organisms are thought to employ them during interspecific interactions, whereas multicellular life forms use them as part of their innate immune systems [36][34]. Despite the economic importance of many crustaceans, AMPs have not been extensively studied in these organisms, and research efforts continue to be channeled into identifying novel AMPs in a range of crustacean species [37][35]. Such efforts are likely to lead to the discovery of new AMPs, which will help to elucidate patterns in the evolution of these peptides in this animal group. To date, six AMPs have been identified in shrimp (order Decapoda, family Penaeidae) and 16 chemically distinct AMPs within the subphylum Crustacea (Table 1).
Table 1. Diversity of AMPs in Crustacea. Entries marked by an asterisk (*) in the third column were determined using the PHI-Blast alignment tool (https://blast.ncbi.nlm.nih.gov/Blast.cgi, accessed on 1 March 2021).
AMP Characteristics Sequence Affinity with Other Animal Taxa Order Family Species References
Bac-like 6.5 kDa, Pro-rich, cationic Fifth iteration, mostly Pro-rich bacterial peptides of unknown functions * Decapoda Carcinidae Carcinus maenas [38][36]
Callinectin 3.7 kDa, Pro/Arg-rich, similar to arasins, cationic No sequence similarity detected * Decapoda Portunidae Callinectes sapidus [39,40][37][38]
Astacidin-2 1.8 kDa, Pro/Arg-rich, cationic Similar to arasin and arasin-like proteins from Scylla spp., Hyas Araneus * Decapoda Astacidae Pacifastacus leniusculus [41][39]
Armadillidin 5.3 kDa, Gly-rich, cationic No sequence similarity detected * Isopoda Armadillidiidae Armadillidium vulgare [42][40]
Homarin (CAP-1) 4–6 kDa, putatively amphipathic α-helical, cationic Similar to amphibian temporins Decapoda Nephropidae Homarus americanus [43][41]
Defensins 6.8–7.2 kDa, contains three disulfide bonds, cationic Shares six putatively homologous Cys residues with mammalian β-defensins Decapoda Palinuridae Panulirus japonicus [44][42]
Anti LPS factor 7–11 kDa, contains a highly hydrophobic N-terminal region and the two Cys residues. The 3D structure of shrimp ALF consists of three α-helices and four-stranded β-sheets; the functional LPS-binding domain is a conserved cluster of positively charged residues within a β-hairpin located between two conserved Cys residues Widely distributed in Crustacea * Decapoda Penaeidae Metapenaeus dobsoni, Penaeus spp. (9) [24,45,46][24][43][44]
Atyidae Neocaridina heteropoda
Palaemonidae Macrobrachium spp. (3), Palaemon carinicauda
Nephropidae Homarus americanus
Parastacidae Cherax quadricarinatus
Astacidae Pacifastacus leniusculus
Cambaridae Procambarus clarkii
Varunidae Eriocheir sinensis
Oregoniidae Cionoecetes opilio
Portunidae Charybdis spp. (2), Portunus spp. (2), Scylla spp. (4)
Amphipoda Hyaelellidae Hyalella azteca
Talitridae Trinorchestia longiramus
Isopoda Armadillidiidae Armadillidium spp. (2)
Scygonadin 10.8 kDa, contains two Cys residues reminiscent of ALFs, anionic Found only in Scylla serrata seminal fluid; shows similarities to ALFs, which might indicate a common evolutionary origin Decapoda Astacidae Scylla serrata [14]
Scylla serrata antimicrobial protein (SSAP) 11.4 kDa, anionic A Scygonadin homolog Decapoda Astacidae Scylla serrata [47][45]
Penaeidin 4.7–7.2 kDa, cationic, N-terminal Pro/Arg-rich domain, C-terminal domain contains an amphipathic helix and

two coils constrained by three disulfide bonds		 Contains at least four subgroups found only in penaeidae shrimp Decapoda Penaeidae Penaeus spp. (12)

Penaeus monoceros		 [16]
Crustin 6–22 kDa, cationic, contains whey acidic protein (WAP) domain, further characterized by Gly-rich regions and conserved Cys residues Found throughout Crustacea, and even in some hymenopterans * Anostraca Artemiidae Artemia salina [16,48][16][46]
Decapoda Penaeidae Penaeus spp. (6)
Atyidae Neocaridina heteropoda
Palaemonidae Macrobrachium nipponense
Pandalidae Pandalus japonicus
Alvinocarididae Rimicaris exoculata
Palinuridae Panulirus spp. (2)
Nephropidae Homarus spp. (2)
Parastasidae Cherax quadricarinatus
Astacidae Pacifastacus leniusculus
Lithodidae Paralithodes camtschaticus
Oregoniidae Hyas araneus
Portunidae Portunus pelagicus

Scylla spp. (3)
Hyastatin 11.7 kDa, cationic, contains a Gly-rich region, Pro-rich domain, and Cys-rich domain High sequence similarity with

SpHyastatin		 Decapoda Oregoniidae Hyas araneus

Cionoecetes opilio		 [49][47]
Portunidae Portunus trituberculatus
SpHyastatin 14.1 kDa, cationic, contains Pro-rich domain and Cys-rich domain High sequence similarity with Hyastatin, but lacking a Gly-rich region Decapoda Portunidae Scylla paramamosain [49][47]
Arasin 4.3–4.8 kDa, cationic, Pro- and Arg-rich Similar to Astacidin-2 Decapoda Oregoniidae Hyas araneus [50][48]
Stylicin 8.9 kDa, multidomain, N-terminal

Pro/Arg-rich domain, C-terminal domain contains 13 Cys residues		 Found only in Penaeidae. Decapoda Penaeidae Penaeus spp. (4)

Penaeus japonicus		 [16]
Pellino-1-derived cationic antimicrobial prawn peptide 8.0 kDa, β-sheet forming, cationic Artificial, based on bioinformatic analyses of the structure of Pellino-1. Decapoda Palaemonidae Macrobrachium rosenbergii [51][49]
Histones or histone-derived peptides Fi-Histidin: 2.9 kDa, enriched in Arg, Ala, Gly, Leu, Ser, cationic, α-helical structure

H2A: 13.2 kDa, cationic

H2B: 13.5 kDa, cationic		 Highly conserved with great sequence similarity; antimicrobial action might be due to sequence at the N-terminus * Decapoda Penaeidae Penaeus spp. (2) [52,53][50][51]
Hemocyanin-derived peptides C-terminus: 7.9–8.3 kDa, anionic, His-rich, α-helical structure

Astacin-1: 1.9 kDa, cationic

Predicted AMPs: 1.5–1.8 kDa		 Highly conserved with great sequence similarity * Decapoda Penaeidae Penaeus spp. (2) [54,55,56][52][53][54]
Astacidae Pacifastacus leniusculus
Cambaridae Procambarus clarkii
Spgly-amp 3.98 kDa, cationic, Gly-rich Known from a single species with a hypothetical protein detected in Portunus trituberculatus, no sequence similarities detected in other Crustacean families *. Decapoda Portunidae Scylla paramamosain [57][55]
Scyreprocin 9.1 kDa, cationic, Lys, Ala and Ser are the most common amino acids Known from a single species with a hypothetical protein detected in Portunus trituberculatus, no sequence similarities detected in other Crustacean families *. Decapoda Portunidae Scylla paramamosain [58][56]
Interestingly, not all of the AMPs are found in all the crustacean groups. While some are found in all Crustacean orders [46][44], hinting at an ancient origin of these molecules, others are limited to one or a few families, thereby suggesting a more recent evolution (Table 1). A good example of an ancient class of AMPs are the ALFs, which have undergone intense diversification. In contrast, penaeidins are a class of AMPs found in a single family of crustaceans, where they have diversified into four distinct subtypes. Therefore, there is a vast diversity of AMPs that could be elucidated through future bioinformatics and proteomic searches [59][57]. Clues as to the causes of the great diversification of some AMPs in the Crustacea subphylum can be found by looking at the amino acid composition. Many AMPs show a clear amino acid bias, being rich in Pro, Pro/Arg, or Gly. These amino acids cause the peptide to acquire certain structures and have a cationic nature (although a few anionic AMPs do exist). These properties predispose the peptides to interact in certain ways with the membrane of pathogens. Thus, some AMPs may have resulted from nonsense mutations in large proteins that have domains rich in these amino acids. Pro-rich proteins are ubiquitous in eukaryotic genomes, and are thus common signaling molecules. In general, Pro/Arg-rich proteins that can provide a blueprint for AMPs are not as common, but they can be found throughout the genomes of several eukaryotic organisms and have diverse functions, such as C9ORF72 [60][58]. However, within the Crustacea subphylum, Pro-rich AMPs have a diverse evolutionary origin [61][59]. Gly-rich proteins are common throughout Eukaryotes and often have diverse functions [62][60]. Prior to the mutations that may have led to the creation of putative “pre-AMPs”, the gene in question would have had to undergo duplication to avoid the loss of functionality. These genes are molecular “hopeful monsters”, resulting in new lineages of selfish genes that confer an important immune advantage to the individual, vis a vis population, in response to pathogens. The proposed model for the diversification of other AMPs would also hold for the truncation of proteins that preserve entire domains, such as the single whey acidic protein (WAP) which contains eight well-conserved cysteine residues forming a four-disulfide core [31]. Truncation of proteins is followed by a nonsense mutation in one or more orthologs, of which only those with antibacterial properties confer an advantage to the animal. These novel AMPs may then have further multiplied through gene duplication and mutation. The observation that the antibacterial activity of AMPs is due to the properties of a certain group of amino acids suggests that the de novo synthesis of artificial AMPs could stem from the search of amino acid sequences with a similar bias or the search for motifs or domains with a heavy bias in the aforementioned amino acids [59][57].

3. Defense Mechanisms in Crustaceans

3.1. Hemocytes

Crustaceans belong to the phylum Arthropoda, and despite not having the sophistication of an adaptive immune system, they have a highly effective innate immune system to fight infections [63][61]. The first lines of crustacean defense are internal and external physical barriers. A strong external cuticle protects the body and the stomach, and the peritrophic membrane covers the midgut and hindgut [64][62]. The circulatory system of crustaceans is open; thus, the circulatory fluid, called hemolymph, flows freely through the circulatory system, which has open endings into the lacunal system (the hemocoel), which is in direct contact with tissues. The hemolymph has two components: cellular and humoral. The former is composed of hemocytes, the main immune effectors of the crustacean immune system. In contrast, several proteins, namely the respiratory pigment hemocyanin, the clotting factor, and several AMPs, among others, make up the humoral component. The crustacean hemolymph performs the functions of both the lymph and blood, and thus its biochemical and cellular components reflect the dual function of this tissue. For example, hemocyanin transports oxygen and participles in the immune response [65,66,67][63][64][65]. The innate immunity of crustaceans consists of a cellular and humoral response. The former involves the hemocytes, classified into three major types: hyaline cells (HCs), large granular cells (LGCs), and small-granular cells (SGCs). These cells exert diverse roles (Wu et al., 2019) as they interact with pathogens. HCs are involved in phagocytosis and coagulation, while SGCs participate in phagocytosis, nodule and capsule formation, and the release of the molecules of the prophenoloxidase (proPO) system and AMPs. LGCs store immune effector molecules, AMPs, and enzymes of proPO [68,69,70][66][67][68]. The proportions of each type of hemocyte in the hemolymph depend on various factors, such as molting [71,72][69][70]. Hemocytes are produced by hemopoietic tissues. In shrimp, these tissues are located as various epigastric lobules, mainly latero-dorsally to the cardiac stomach and in the proximal region of the maxillipeds. Hemopoietic hemocyte growth and differentiation is likely to be mediated by cytokines [68,73,74][66][71][72].

3.2. Cellular Reactions

Given the open nature of the shrimp circulatory system, hemocytes easily infiltrate tissues, and can respond in a localized way or migrate to specific tissues (gills, lymphoid organs, and connective tissue), where they trigger cellular reactions or release a range of compounds. The cellular reaction includes phagocytosis, which is performed mainly by HCs and SGCs, and is accompanied by degradative reactions via the generation of lytic enzymes or reactive oxygen or nitrogen species (ROS and RNS) generated during the respiratory burst [75][73]. In response to massive invasions of microorganisms or large microorganisms, hemocytes form cell aggregations called nodules. Denser cell aggregations made up of several layers of hemocytes are known as capsules. Sometimes, nodules or tubules of the hepatopancreas (invaded by Vibrio spp.) appear to be encapsulated by hemocytes. Melanin, a sticky and toxic dark pigment, is deposited in a very localized way in the central areas of nodules and capsules, or in wounds during the healing process. Melanin is generated by phenoloxidase, an enzyme that is produced via the activation of proPO system. The proPO system, one of the main immunoeffector responses of crustaceans, comprises a series of enzymatic cascade reactions [76][74] triggered by components of the cell walls of microorganisms, such as β-1,3-glucans from fungi, or lipopolysaccharide (LPS) and peptidoglycans from Gram-negative and Gram-positive bacteria, respectively [77][75]. Melanin formation generates intermediate reactive compounds (quinones and ROIS), which are more toxic than melanin. ProPO oxidase is regulated by several protease inhibitors, among them, pacifastina and α2-macroglobulin, produced by HCs. α2-macroglobulin inhibits serine proteases of the proPO cascade, and possibly pathogen proteases [78][76]. Hemocytes also participate in another cellular reaction, namely, extracellular traps (ETs). This process involves the formation of DNA structures and AMPs to trap microorganisms. In the shrimp Marsupenaeus japonicus, ETs associated with c-type lysozyme have been described [79][77].

3.3. Other Immune Tissues

In addition to hemocytes, other tissues of the penaeid shrimp are involved in the immune response, including the heart reserve of phagocytes the podocytes of the gills, antennal gland, and the lymphoid organ (LO). The latter, which is near the hepatopancreas, receives hemolymph from the subgastric artery that forms a vascular plexus within this structure. The LO appears to filter viruses from the hemolymph [80][78]. Very strong hemocyte infiltration is detected in the LO, contributing to the immune functions of this organ. Many genes and molecules associated with hemocytes have been reported in the LO [80,81][78][79]. In this regard, a strong signal of penaeidin and α2-macroglobulin has been detected in the edges of tubules of the LO, in the same zone that participates in virus filtration. During infection, mainly that of viral etiology, nodular hyperplasia, known as LO spheroids (LOS) appear in the LO. These hyperplasic cells show a positive signal toward penaeidin and α2-macroglobulin [80][78]. It has been outlined that LOS are involved in the phagocytosis and destruction of foreign particles [82][80]. Terminal type C LOS exhibits an apoptosis signal, thus indicating the fate of engulfed material. Ectopic spheroids have also been detected in the connective tissues of other organs (stomach and buccal appendages). Initially, there was some controversy regarding whether apoptosis as a response to viral infections in shrimp was a defense mechanism or a pathogenicity mechanism triggered by the virus [83][81]. The literature has reported that in the early stages of white spot syndrome virus (WSSV) infection, the virus exerts a mechanism to prevent host cells from entering apoptosis [84][82]. This observation thus indicates that apoptosis is a mechanism associated with the host’s immune response.

3.4. Humoral Response

Humoral effectors involve the synthesis and secretion of immune proteins such as AMPs from hemocytes into the hemocoel. Part of the humoral response is the clotting system, which is stimulated by injuries and by the binding of microbial stimulants, such as β-1,3-D-glucans, to receptors on hemocytes. These cells release Ca2+-dependent transglutaminases, which promote the polymerization of clotting proteins [85][83]. Finally, proteins derived from hemocyanin and hemocyanin-derived proteins have multiple functions in the hemolymph, from oxygen transport, antimicrobial activity, and agglutination, to playing a major role in the proPO system [65,66,67,85][63][64][65][83]. The multiple roles of hemocyanin-related proteins, as well as the diversity of AMP families, suggest that gene duplication and subsequent functional diversification are an important feature of the crustacean immune response. The open nature of the circulatory system of crustaceans, which is composed of vessel systems and a system of lacunae and sinuses surrounding the most important organs [86][84], facilitates the rapid migration and infiltration of hemocytes in different tissues, where they can then release their molecules in a localized manner.

3.5. Recognition of Foreign Molecules

Recognition molecules, including various types of lectins, galectins, β-1,3-glucanase-related protein, Toll-like receptors (TLR), Thioester-containing proteins (TEPs), scavenger receptors, Down syndrome adhesion molecules, and fibrinogen-related proteins, can circulate freely in the hemolymph or be bound to cell membranes. These molecules are able bind to pathogen-associated molecular patterns (PAMPs). Thus, signaling cascades in hemocytes are triggered, leading to the production and exocytosis of AMPs [87][85] and lysozymes, as well the activation of the proPO system.

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