Defensins are the most characterised group of AMPs in both vertebrates and invertebrates, though no pure fractions of mollusc defensins have successfully been tested for antiviral activity. MGD-1, first isolated in M. galloprovincialis, is approximately 39 aa long and exhibits a common motif in defensins, termed an alpha-beta loop, consisting of an α-helix and two β-sheets [50,51]. Additionally, MGD-1 inhibits the growth of many Gram-positive bacteria by binding to lipid II, a precursor to peptidoglycan [50,52]. Though not tested for antiviral defence in molluscs, a 10 amino acid long fragment of MGD-1 has been demonstrated to inhibit mortality in the Chelicerate Palaemon serratus against White Spot Syndrome Virus by directly binding to and disrupting viral envelopes [44,53]. In these studies, a 10 amino acid long fragment of MGD-1 constrained by two disulphide bonds in a stable beta hairpin structure was shown to be the critical domain required for viral inhibition [44]. Moreover, MGD-1 breaks the conformity of other defensins such as the antibacterial MGD-2, possessing two additional C-domains, which is suggestive of a greater spectrum of molecular functions and renders the structure similar to Mytilus genus AMPs [44,51].

Big defensins are, as the word suggests, structurally larger (70–180 aa) than defensins, and possess both C-domains and an N-terminal [6,54]. Big defensins are believed to have given rise to vertebrate β-defensins, which lost the N-terminal during evolution from basal chordates to vertebrates [54]. The additional N-terminal of big defensins often provides additional protein functions, including antimicrobial activity [54]. To date, the mollusc big defensins have all only been tested for antibacterial and antifungal activity, including the three described in C. gigas; Cg-BigDef1, Cg-BigDef2, and Cg-BigDef3 [52,55]. Specifically, these three big defensins are active against both Gram-negative and Gram-positive species, and also exhibit bactericidal activity against Staphylococcous aureus multiresistant to antibiotics and Vibrio spp., by disrupting bacterial membranes through hydrophobic interactions [41,54].

Very few investigations have described big defensin diversity or gene organization, thus it is possible that there are yet undiscovered mollusc defensins that contain antimicrobial roles, including antiviral activity, which may be harnessed to manufacture both invertebrate and human infection treatments.

Mytilus AMPs are those peptides isolated solely in members of the mollusc genus Mytilus [56]. These AMPs include the classes myticins, mytilins, mytimycins, and mytimacins [56]. All three identified myticins have expressed antibacterial and antifungal activity, but only myticin-C possesses antiviral activity [56]. Myticin-C has gained the most attention for a single AMP, for its various roles in innate immunity. First isolated in the Blue Mussel (M. galloprovincialis), cysteine-rich AMP prevents the viral replication of OsHV-1 in molluscs and, interestingly, HSV-2 in humans [56]. Myticin-C was also shown to play a role in danger signaling, and is upregulated in response to tissue damage in M. galloprovinicalis [57]. Interestingly, myticin-C expresses a high nucleotide sequence variability across more than 100 mussels, perhaps suggesting that it is derived from a more ancient and common nucleotide sequence, and due to its highly conserved and ubiquitous nature, may play additional roles in innate immunity [58].

The five mytilin AMPs protect against bacterial and fungal infections, however, their antiviral roles are currently unknown [59]. Of the AMP class, mytilin-B is the most researched, due to its potent defensive roles against Gram-positive bacteria in Mytilus edulis [60]. It has been determined that mytilin-B contains an α-helix linked by four disulfide bridges to two β-sheets [61]. Though mytilin-B has not been tested for antiviral activity in molluscs, a 13 amino-acid-long fragment of one disulfide bridge and an acid loop structure has been tested against White Spot Syndrome Virus in the prawn, P. serratus [53]. The study found that the fragment, designed to mimic a common sequence found in defensins, offered minimal protection and animals died four days post challenge [53]. In comparison, whole mytilin-B provided an approximate 70% survival rate for 13 days post challenge, suggesting the mytilin-B possesses a separate structural attribute to other defensins that provides antimicrobial defence [53]. The structurally similar mytilin-A is also shown to inhibit herpes simplex virus-1 (HSV-1) replication during in vitro experiments, due to a dense cysteine-rich structure that competes for binding sites, and thus prevents viral attachment [60]. Therefore, it is possible mytilin-B and mytilin-A possess unknown antiviral roles in the Mytilus genus, the description of which may yield a broad spectrum of antimicrobial defence for all molluscs.

Mytimycins and mytimacins are the least studied Mytilus genus AMPs and display antibacterial and antifungal activity, though they have not been tested for antiviral activity [6,62]. Mytimycins and mytimacins are generally larger than other Mytilus genus AMPs and defensins, at approximately 80–100 aa [6,61]. They have been shown to possess ten C-domains, which is more than any other Mytilus AMP [63], and as C-domains are related to peptide function, it is likely that the structurally similar mytimycins and mytimacins possess currently undescribed antiviral activity, which should be the focus of future studies [6].

Hemocyanins (Hcs) constitute 50–90% of hemolymph and are copper-containing glycoproteins that transport oxygen, possess antimicrobial activity, and have C-domains that encode for peptides with AMP-like activity [64,65]. The antimicrobial activity of Hcs and equivalent glycoproteins, such as cavortin in C. gigas, include antiviral defence, as demonstrated by in vitro assays involving HSV-1 [66,67]. Purified abalone Hc (from Haliotis rubra), has been shown to bind to specific viral surface glycoproteins of HSV-1, inhibiting viral attachment and entry into Vero cells in vitro, however, it displayed no antiviral activity when added to the culture post HSV-1 infection [66].

The C-domain of Hcs encode for many Hc derived peptides (Hcdps), such as the highly conserved haliotisin, which is present in many of molluscs [68]. The C-domain of other proteins have been shown to encode for peptides with AMP-like activity, such as histone H2A in the abalone Haliotis discus discus, which encodes for the peptide abhisin [69]. Such domain-encoded peptides with AMP-like activity have only been tested for antibacterial and antifungal activity, with no investigations into antiviral properties. As these domain-encoded peptides are still relatively novel, investigations into their function remain very limited, and future research will hopefully include antiviral activity screens.

AMPs represent hopeful prospects for future mollusc innate-immunity studies, due to their highly conserved regions that aid in describing previously undiscovered peptides, as well as their role in antimicrobial defence. Moreover, AMP applications reach beyond mollusc innate immunity, and include the possibility of being repurposed to produce higher order species of antimicrobial compounds. Thus, investigations into mollusc AMPs are vital and should include a broader description of the functions and structures of currently undescribed peptides, and should also incorporate structural knowledge of AMPs to discover novel molecules.