Structural Diversity and Biological Activities of Fungal Cyclic Peptides, Excluding Cyclodipeptides

Cyclic peptides are cyclic compounds formed mainly by the amide bonds between either proteinogenic or non-proteinogenic amino acids. This review highlights the occurrence, structures and biological activities of fungal cyclic peptides (excluding cyclodipeptides, and peptides containing ester bonds in the core ring) reported until August 2017. About 293 cyclic peptides belonging to the groups of cyclic tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, dodeca-, tetradeca-, and octadecapeptides as well as cyclic peptides containing ether bonds in the core ring have been isolated from fungi. They were mainly isolated from the genera Aspergillus, Penicillium, Fusarium, Acremonium and Amanita. Some of them were screened to have antimicrobial, antiviral, cytotoxic, phytotoxic, insecticidal, nematicidal, immunosuppressive and enzyme-inhibitory activities to show their potential applications. Some fungal cyclic peptides such as the echinocandins, pneumocandins and cyclosporin A have been developed as pharmaceuticals.


Introduction
Cyclic peptides (also called cyclopeptides) are cyclic compounds formed mainly by proteinogenic or non-proteinogenic amino acids joined together by amide bonds (or peptide bonds). Cyclic peptides have been isolated from plants [1], fungi [2], bacteria (including actinomycetes) [3], sponges [4], algae [5,6], and mammals [7]. Among these organisms, fungi are well-known producers of a diversity of cyclic peptides with interesting structures and biological activities [8]. Here, we focus on the cyclic peptides derived from fungi, including insect pathogenic fungi, plant pathogenic fungi, soil-derived fungi, marine-derived fungi, plant or insect endophytic fungi, and the macroscopic fungi which we usually call mushrooms. Some of the fungal cyclic peptides are mycotoxins which pose a hazard to animals and plants [2]. Interest in cyclic peptides is due to their significant biological activities, such as antimicrobial, insecticidal, cytotoxic, and anticancer activities, in addition to their important physiological and ecological functions. Therefore, they have the potential to be developed as pharmaceuticals and agrochemicals [9].
Fungal cyclic peptides mainly include cyclic di-, tri-, tetra-, penta-, hexa-, hepta-, octa-, nona-, and decapeptides. Recent special reviews covering the chemical synthesis [10], biosynthesis [11,12], as well as developments and applications (i.e., echinocandins, pneumocandins and cyclosporin A) [13,14] of fungal cyclic peptides are available. In this review, we describe the occurrence, biological activities, structures, and potential applications of the fungal cyclic peptides and their analogs, with the exception of cyclodipeptides (called 2,5-diketopiperazines), which were previously reviewed [15]. Cyclic depsipeptides from organisms including fungi, which are a big group of cyclic peptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one Table 1. Fungal cyclic tripeptides and their biological activities.

Name
Fungus and its Origin Biological Activity Ref.

Cyclic Tetrapeptides
Cyclic tetrapeptides have been found in many genera such as Acremonium, Alternaria, Cylindrocladium, Fusarium, Helicoma, Penicillium, Peniophora, Phoma, Phomopsis, Pseudoxylaria, Stachylideium, and Verticillium. Their origins and biological activities are listed in Table 2, and the corresponding structures are shown in Figure 2.
AS1387392 (36) from Acremonium sp. No. 27082 showed a strong inhibitory effect against mammalian HDAC and T-cell proliferation which suggested its potential as immunosuppressant [37].
Asperterrestide A (38) from the fermentation broth of the marine-derived fungus Aspergillus terreus SCSGAF0162 showed cytotoxicity against U937 and MOLT4 hunman carcinoma cell lines and inhibitory effects on influenza virus strains H1N1 and H3N2 [38].
Cyl-1 (51) and Cyl-2 (52) from the plant fungal pathogen Cylindrocladium scoparium exhibited marked inhibition on the growth of rice and lettuce seedlings, especially on their root growth, which suggested that they could be used to inhibit plant growth [45,46].
Microsporins A (66) and B (67) from the marine-derived fungus Microsporum cf. gypseum CNL-692 obtained from a sample of the bryozoan Bugula sp. collected in the U.S. Virgin Islands. Both compounds showed inhibitory activity on HDAC and demonstrated cytotoxic activity against human colon adenocarcinoma (HCT-116) cells [47].

Name
Fungus and Its Origin Biological Activity Ref.

Cyclic Pentapeptides
Cyclic pentapeptides have been mainly isolated from the genera of Aspergillus, Fusarium, Hamigera, Penicillum, Pseudallescheria and Xylaria. Their distributions in fungi, and biological activities are listed in Table 3, and the structures are provided in Figure 3.
Argadin (86) and argifin (87) produced by Clonostachys sp. FO-7314 and Gliocladium sp. FTD-0668, respectively, were identified in screening as chitinase inhibitors [81,82]. Chitinases play key roles in organisms, ranging from bacteria to humans. There is a need for specific, potent inhibitors to probe the function of these chitinases in different organisms. Such molecules could also provide leads for the development of chemotherapeuticals with fungicidal, insecticidal, or anti-inflammatory potential. Argadin (86) and argifin (87) could be used as the leads for the development of novel chitinase inhibitors [83].
Aspergillipeptide D (88) was isolated from the marine gorgonian-derived fungus Aspergillus sp. SCSIO 41501. It showed evident antiviral activity against herpes simplex virus type 1 (HSV-1) with a median inhibitory concentration (IC 50 ) value of 9.5 µM under their non-cytotoxic concentration against a Vero cell line, and also had antiviral activity against acyclovir-resistant clinical isolates of HSV-1 [84].

Cyclic Hexapeptides
About 40 cyclic hexapeptides have been isolated from fungi. Their distributions in fungi, and biological activities are shown in Table 4, and the structures are provided in Figure 4.
The echinocandins have emerged as first-line antifungal agents for many Candida and Aspergillus infections. They have a unique mechanism of action by inhibiting the synthesis of β-1,3-D-glucan, a key component of the fungal cell wall. Caspofungin was the first echinocandin antifungal agent to become licensed for treatment of invasive fungal infecitons [119]. Caspofungin has been used in immunocompromised children and neonates with invasive fungal infections [120]. The second

Cyclic Hexapeptides
About 40 cyclic hexapeptides have been isolated from fungi. Their distributions in fungi, and biological activities are shown in Table 4, and the structures are provided in Figure 4.
The echinocandins have emerged as first-line antifungal agents for many Candida and Aspergillus infections. They have a unique mechanism of action by inhibiting the synthesis of β-1,3-D-glucan, a key component of the fungal cell wall. Caspofungin was the first echinocandin antifungal agent to become licensed for treatment of invasive fungal infecitons [119]. Caspofungin has been used in immunocompromised children and neonates with invasive fungal infections [120]. The second commercial antifungal agent in the echinocandin series was micafungin which has been used worldwide in chemotherapy for life-threatening fungal infections [121].

Cyclic Heptapeptides
There are 37 cyclic heptapeptides isolated from fungi. Their distributions in fungi, and biological activities are listed in Table 5, and the structures are shown in Figure 5.

Cyclic Heptapeptides
There are 37 cyclic heptapeptides isolated from fungi. Their distributions in fungi, and biological activities are listed in Table 5, and the structures are shown in Figure 5.

Cyclic Octapeptides
The distributions and biological activities of fungal cyclic octapeptides are listed in Table 6, and the structures are shown in Figure 6.
Fungal cyclic octapeptides mainly include the amatoxins, which are bicyclic octapeptides distributed in the poisonous mushroom Amanita phalloides. Nine amatoxin analogs amanin (214), amanin amide (215), amanullin (216), amanullinic acid (217), α-amanitin (218), β-amanitin (219), γ-amanitin (220), ε-amanitin (221), and proamanullin (225) have been identified [150]. The most important biochemical effect of amatoxins is the inhibition of RNA polymerases (especially polymerase II). This interaction leads to a tight complex, and the inhibition is of a non-competitive type. Non-mammalian polymerases show little sensitivity to amanitins. The amatoxins cause necrosis of the liver, also partly in the kidney, with the cellular changes causing the fragmentation and segregation of all nuclear components. Various groups of somatic cells of emanation resistance have been isolated, including from a mutant of Drosophila melanogaster [150].
Amatoxins are synthesized as proproteins on ribosomes, and are considered as ribosomally synthesized and post-translationally modified peptides (RiPPs). The proproteins are 34-35 amino acids in length and do not have predicted signal peptides [151].
Epichlicin (222) was isolated from the endophytic fungus Epichloe typhina from the timothy plant (Pheum pretense). This compound exhibited inhibitory activity toward the spore germination of Cladosporium phlei, a fungal pathogen of the timothy plant at an IC50 value of 22 nM [166].

Name
Fungus and Its Origin Biological Activity Ref.

Cyclic Octapeptides
The distributions and biological activities of fungal cyclic octapeptides are listed in Table 6, and the structures are shown in Figure 6.
Fungal cyclic octapeptides mainly include the amatoxins, which are bicyclic octapeptides distributed in the poisonous mushroom Amanita phalloides. Nine amatoxin analogs amanin (214), amanin amide (215), amanullin (216), amanullinic acid (217), α-amanitin (218), β-amanitin (219), γ-amanitin (220), ε-amanitin (221), and proamanullin (225) have been identified [150]. The most important biochemical effect of amatoxins is the inhibition of RNA polymerases (especially polymerase II). This interaction leads to a tight complex, and the inhibition is of a non-competitive type. Non-mammalian polymerases show little sensitivity to amanitins. The amatoxins cause necrosis of the liver, also partly in the kidney, with the cellular changes causing the fragmentation and segregation of all nuclear components. Various groups of somatic cells of emanation resistance have been isolated, including from a mutant of Drosophila melanogaster [150].
Amatoxins are synthesized as proproteins on ribosomes, and are considered as ribosomally synthesized and post-translationally modified peptides (RiPPs). The proproteins are 34-35 amino acids in length and do not have predicted signal peptides [151].
Epichlicin (222) was isolated from the endophytic fungus Epichloe typhina from the timothy plant (Pheum pretense). This compound exhibited inhibitory activity toward the spore germination of Cladosporium phlei, a fungal pathogen of the timothy plant at an IC 50 value of 22 nM [166].

Name
Fungus and Its Origin Biological Activity Ref.

Cyclic Nonapeptides
Only four cyclic nonapeptides have been identified in fungi, with their occurrence, biological activities and structures shown in Table 7 and Figure 7, respectively. Amanexitide (227) was isolated from the fruiting bodies of Amanita exitialis, a poisonous mushroom endemic in China [168]. Both clonostachysins A (228) and B (229) were obtained from a marine sponge-derived fungus Clonostachys rogersoniana strain HJK9. They exhibited a selectively inhibitory activity on the dinoflagellate Prorocentrum micans at 30 μM [170]. Cylindrocyclin A (230) from Cylindrocarpon sp. exhibited cytotoxic activity against six cell lines with IC50 values ranging from 11 to 53 μM [171].

Cyclic Nonapeptides
Only four cyclic nonapeptides have been identified in fungi, with their occurrence, biological activities and structures shown in Table 7 and Figure 7, respectively. Amanexitide (227) was isolated from the fruiting bodies of Amanita exitialis, a poisonous mushroom endemic in China [168]. Both clonostachysins A (228) and B (229) were obtained from a marine sponge-derived fungus Clonostachys rogersoniana strain HJK9. They exhibited a selectively inhibitory activity on the dinoflagellate Prorocentrum micans at 30 µM [170]. Cylindrocyclin A (230) from Cylindrocarpon sp. exhibited cytotoxic activity against six cell lines with IC 50 values ranging from 11 to 53 µM [171].

Cyclic Decapeptides
A total of seven cyclic decapeptides were identified in fungi. Their distributions, biological activities and structures are shown in Table 8 and Figure 8.
Antamanide (231) derived from the fungus Amanita phalloides inhibited the mitochondrial permeability transition pore, a central effector of apoptosis induction, by targeting the pore regulator cyclophillin D [172].

Cyclic Decapeptides
A total of seven cyclic decapeptides were identified in fungi. Their distributions, biological activities and structures are shown in Table 8 and Figure 8.
Antamanide (231) derived from the fungus Amanita phalloides inhibited the mitochondrial permeability transition pore, a central effector of apoptosis induction, by targeting the pore regulator cyclophillin D [172].

Cyclic Decapeptides
A total of seven cyclic decapeptides were identified in fungi. Their distributions, biological activities and structures are shown in Table 8 and Figure 8.
Antamanide (231) derived from the fungus Amanita phalloides inhibited the mitochondrial permeability transition pore, a central effector of apoptosis induction, by targeting the pore regulator cyclophillin D [172].

Cyclic Undecapeptides
Twenty-six cyclosporin analogs were identified in fungi. They belong to the cyclic undecapeptide group, and their distributions, biological activities and structures are shown in Table 9 and Figure 9, respectively.
Among them, cyclosporin A (238) has received the most meticulous attention owing to its immunosuppressive and antifungal activity [176]. Cyclosporin A (238) can be produced by a series of fungi such as Aspergillus fumigatus [177], Aspergillus terreus [178], Beauveria nivea [179], Fusarium oxysporum [180], Trichoderma polysporum [181], Tolypocladium inflatum [182], and Tolypocladium sp. [183]. It was mainly produced by various types of fermentation techniques using Tolypocladium inflatum. It has a variety of biological activities including immunosuppressive, anti-inflammatory, antifungal and antiparasitic properties. The mechanism of action has been considered as the phosphatase activity inhibition of calcineurin, and production of IL-2 and other cytokines [176]. FR901459 (263), a derivative of cyclosporin A (238), was discovered in the fermentation broth of Stachybotrys chartarum No. 19392 (isolated from soil collected in Tokyo Prefecture, Japan). This compound showed antifungal activity, and was capable of prolonging the survival time of skin allografts in rats with one-third the potency of cyclosporin A [184]. It also prevented mitochondrial swelling and protected against delayed neuronal cell death [185].

Cyclic Undecapeptides
Twenty-six cyclosporin analogs were identified in fungi. They belong to the cyclic undecapeptide group, and their distributions, biological activities and structures are shown in Table 9 and Figure 9, respectively. Among them, cyclosporin A (238) has received the most meticulous attention owing to its immunosuppressive and antifungal activity [176]. Cyclosporin A (238) can be produced by a series of fungi such as Aspergillus fumigatus [177], Aspergillus terreus [178], Beauveria nivea [179], Fusarium oxysporum [180], Trichoderma polysporum [181], Tolypocladium inflatum [182], and Tolypocladium sp. [183]. It was mainly produced by various types of fermentation techniques using Tolypocladium inflatum. It has a variety of biological activities including immunosuppressive, anti-inflammatory, antifungal and antiparasitic properties. The mechanism of action has been considered as the phosphatase activity inhibition of calcineurin, and production of IL-2 and other cytokines [176]. FR901459 (263), a derivative of cyclosporin A (238), was discovered in the fermentation broth of Stachybotrys chartarum No. 19392 (isolated from soil collected in Tokyo Prefecture, Japan). This compound showed antifungal activity, and was capable of prolonging the survival time of skin allografts in rats with one-third the potency of cyclosporin A [184]. It also prevented mitochondrial swelling and protected against delayed neuronal cell death [185].

Cyclic Tetradecapeptides
Only four cyclic tetradecapeptides, verrucamides A-D (273-276), were identified from the plant pathogenic fungus Myrothecium verrucaria that attacked important crop plants and weeds. Their distributions, biological activities and structures are shown in Table 11 and Figure 11, respectively. They were screened to show antibacterial activity against Staphylococcus aureus [200].

Cyclic Tetradecapeptides
Only four cyclic tetradecapeptides, verrucamides A-D (273-276), were identified from the plant pathogenic fungus Myrothecium verrucaria that attacked important crop plants and weeds. Their distributions, biological activities and structures are shown in Table 11 and Figure 11, respectively. They were screened to show antibacterial activity against Staphylococcus aureus [200].  Figure 11. Structures of the cyclic tetradecapeptides isolated from fungi.

Cyclic Octadecapeptides
Only two highly N-methylated cyclic octadecapeptides namely gymnopeptides A (277) and B (278) were isolated from the mushroom Gymnopus fusipes (Table 12 and Figure 12). They exhibited striking antiproliferative activity on several human cancer cell lines [201]. So far, gymnopeptides A (277) and B (278), constituted by 18 monomers, are the largest cyclic peptides to be isolated from fungi. Fortunately, the total synthesis of gymnopeptides A (277) and B (278) has been achieved [202]. Further biological studies are needed to clarify the aspects of absorption and metabolism of gymnopeptides A (277) and B (278) after consumption of the fruiting bodies by humans, as well as to explore the potential role of these metabolites in the parasitic lifestyle of the mushroom G. fusipes.  Figure 11. Structures of the cyclic tetradecapeptides isolated from fungi.

Cyclic Octadecapeptides
Only two highly N-methylated cyclic octadecapeptides namely gymnopeptides A (277) and B (278) were isolated from the mushroom Gymnopus fusipes (Table 12 and Figure 12). They exhibited striking antiproliferative activity on several human cancer cell lines [201]. So far, gymnopeptides A (277) and B (278), constituted by 18 monomers, are the largest cyclic peptides to be isolated from fungi. Fortunately, the total synthesis of gymnopeptides A (277) and B (278) has been achieved [202]. Further biological studies are needed to clarify the aspects of absorption and metabolism of gymnopeptides A (277) and B (278) after consumption of the fruiting bodies by humans, as well as to explore the potential role of these metabolites in the parasitic lifestyle of the mushroom G. fusipes.

Cyclic Peptides Containing Ether Bonds in the Core Ring
This group of cyclic peptides contained at least one ether linkage except the normal amide and carbon-carbon bonds in the core ring of each molecule. Their distributions, biological activities and structures are shown in Table 13 and Figure 13, respectively.
Asperipin-2a (279) containing five amino acids was isolated from Aspergillus flavus. It was a bicycle peptide containing two ether linkages that was converted from the repeated sequence containing aromatic residues [203].
HV-toxin M (282), with phytotoxic activity, was isolated from the plant pathogenic fungus Cochliobus victoriae (previously as Helminthosporium victoria) from oat (Avena sativa). This compound had three amino acids in the core rings, and two amino acids linked and attached as the side chains [204].
Ustiloxins (286-291) have a 13-membered ring including a phenol ether linkage. They were isolated from the water extract of the false smut balls caused by Ustilaginoidea virens on the panicles of rice plants [208][209][210][211][212]. There are three amino acids in the core ring for each ustiloxin. For ustiloxins C (288), D (289), F (290) and G (291), there is a glycine in the side chain. For ustiloxins A (286) and B (287), there are two amino acids in the side chains, whose tyrosine was modified with norvaline, a non-proteinogenic amino acid. They are biosynthesized by the ribosome, and are ribosomally synthesized and post-translationally modified peptides (RiPPs). The cluster possessed a gene, termed ustA, whose translated product, UstA, contained a 16-fold repeated peptide embedding a tetrapeptide, Tyr-Ala-Ile-Gly, that was converted into the cyclic moiety of ustiloxin B (287) [213]. Through gene inactivation, heterologous expression, and in vitro functional analyses the entire biosynthetic pathway of the ustiloxins was unveiled to involve at least nine enzymes. The oxidative cyclization of the core peptide is not clear yet though [214].

Cyclic Peptides Containing Ether Bonds in the Core Ring
This group of cyclic peptides contained at least one ether linkage except the normal amide and carbon-carbon bonds in the core ring of each molecule. Their distributions, biological activities and structures are shown in Table 13 and Figure 13, respectively.
Asperipin-2a (279) containing five amino acids was isolated from Aspergillus flavus. It was a bicycle peptide containing two ether linkages that was converted from the repeated sequence containing aromatic residues [203].
HV-toxin M (282), with phytotoxic activity, was isolated from the plant pathogenic fungus Cochliobus victoriae (previously as Helminthosporium victoria) from oat (Avena sativa). This compound had three amino acids in the core rings, and two amino acids linked and attached as the side chains [204].
Ustiloxins (286-291) have a 13-membered ring including a phenol ether linkage. They were isolated from the water extract of the false smut balls caused by Ustilaginoidea virens on the panicles of rice plants [208][209][210][211][212]. There are three amino acids in the core ring for each ustiloxin. For ustiloxins C (288), D (289), F (290) and G (291), there is a glycine in the side chain. For ustiloxins A (286) and B (287), there are two amino acids in the side chains, whose tyrosine was modified with norvaline, a non-proteinogenic amino acid. They are biosynthesized by the ribosome, and are ribosomally synthesized and post-translationally modified peptides (RiPPs). The cluster possessed a gene, termed ustA, whose translated product, UstA, contained a 16-fold repeated peptide embedding a tetrapeptide, Tyr-Ala-Ile-Gly, that was converted into the cyclic moiety of ustiloxin B (287) [213]. Through gene inactivation, heterologous expression, and in vitro functional analyses the entire biosynthetic pathway of the ustiloxins was unveiled to involve at least nine enzymes. The oxidative cyclization of the core peptide is not clear yet though [214].

Conclusions and Future Perspectives
In this review, we describe the progress on the chemistry and biological activities of the cyclic peptides (excluding cyclic dipeptides and peptides containing ester bonds in the core ring) discovered from fungi during the past 50 years, especially the recent 20 years.
It seems that the fungi in genus Aspergillus can produce various types of cyclic peptides, especially cyclic tripeptides to pentapeptides, while the mushrooms, which we call macroscopic fungi, produce relatively big cyclic peptides such as amanin (an octapeptide), amanexitide (a nonapeptide), antamanide (decapeptide), omphalotins (dodecapeptide), and gymnopeptides (octadecapeptides). Most of cyclosporins, which belong to the cyclic undecapeptides, show immunosuppressive and antifungal activities. The isolated cyclic dodecapeptides have nematicidal activity, tetradecapeptides possess antibacterial activity, and octadecapeptides show antiproliferative activity on several human cancer cell lines. The cyclic peptides with a big ring seem to display more biological activities than the small-ring peptides.
Some cyclic peptides have been developed as drugs, which are listed in Table 13. One noteworthy example is caspofungin which has strong antifungal activity. Caspofungin is a semisynthetic derivative of pneumocandin B0 (170), a lipophilic cyclic hexapeptide from the fungus Glarea lozoyensis. It was commercialized as the antifungal drug caspofungin acetate (CANCIDAS ® ) which has subsequently saved thousands of lives [14]. Micafungin was the second approved antifungal agent in the echinocandin series, and has been used worldwide in chemotherapy for life-threatening fungal infections. Micafungin is an inhibitor of 1,3-β-glucan synthase, an enzyme necessary for cell-wall synthesis of several fungal pathogens [121]. Other application examples included cyclosporin A (238), an immunosuppressant isolated from Tolypocladium inflatum [176]; omphalotin A (264), a potent nematicidal agent from Omphalotus olearius [197]; and the echinocandins, antifungal lipopeptides

Conclusions and Future Perspectives
In this review, we describe the progress on the chemistry and biological activities of the cyclic peptides (excluding cyclic dipeptides and peptides containing ester bonds in the core ring) discovered from fungi during the past 50 years, especially the recent 20 years.
It seems that the fungi in genus Aspergillus can produce various types of cyclic peptides, especially cyclic tripeptides to pentapeptides, while the mushrooms, which we call macroscopic fungi, produce relatively big cyclic peptides such as amanin (an octapeptide), amanexitide (a nonapeptide), antamanide (decapeptide), omphalotins (dodecapeptide), and gymnopeptides (octadecapeptides). Most of cyclosporins, which belong to the cyclic undecapeptides, show immunosuppressive and antifungal activities. The isolated cyclic dodecapeptides have nematicidal activity, tetradecapeptides possess antibacterial activity, and octadecapeptides show antiproliferative activity on several human cancer cell lines. The cyclic peptides with a big ring seem to display more biological activities than the small-ring peptides.
Some cyclic peptides have been developed as drugs, which are listed in Table 13. One noteworthy example is caspofungin which has strong antifungal activity. Caspofungin is a semisynthetic derivative of pneumocandin B 0 (170), a lipophilic cyclic hexapeptide from the fungus Glarea lozoyensis. It was commercialized as the antifungal drug caspofungin acetate (CANCIDAS ® ) which has subsequently saved thousands of lives [14]. Micafungin was the second approved antifungal agent in the echinocandin series, and has been used worldwide in chemotherapy for life-threatening fungal infections. Micafungin is an inhibitor of 1,3-β-glucan synthase, an enzyme necessary for cell-wall synthesis of several fungal pathogens [121]. Other application examples included cyclosporin A (238), an immunosuppressant isolated from Tolypocladium inflatum [176]; omphalotin A (264), a potent nematicidal agent from Omphalotus olearius [197]; and the echinocandins, antifungal lipopeptides isolated from Glarea lozoyensis, Coleophoma empetri, and Aspergillus nidulans var. echinulatus [219]. Commercial cyclic peptide-derived drugs are listed in Table 14. It is worth mentioning that many fungal cyclic peptides have been isolated from plant endophytic and marine-derived fungi, which indicates that plant endophytic and marine-drived fungi are mines of biologically active natural products [222][223][224][225][226]. Although the number of fungal cyclic peptides is gradually increasing, it remains a group of natural products with relatively little skeletal diversity. On many occasions, the relative or absolute configurations of the chiral centers have not been determined yet. This remains a challenge for future chemical and spectroscopic work. Many isolated cyclic peptides have not been screened for their biological activities as the quantities obtained were very limited. Even fewer compounds have been the subject of systematic investigations to establish structure-activity relationships. Further high throughput screening of biological activities as well as detailed studies on the action mechanisms of fungal cyclic peptides are needed.