Marine Cyclic Peptides: Antimicrobial Activity and Synthetic Strategies

Abstract

Oceans are a rich source of structurally unique bioactive compounds from the perspective of potential therapeutic agents. Marine peptides are a particularly interesting group of secondary metabolites because of their chemistry and wide range of biological activities. Among them, cyclic peptides exhibit a broad spectrum of antimicrobial activities, including against bacteria, protozoa, fungi, and viruses. Moreover, there are several examples of marine cyclic peptides revealing interesting antimicrobial activities against numerous drug-resistant bacteria and fungi, making these compounds a very promising resource in the search for novel antimicrobial agents to revert multidrug-resistance. This review summarizes 174 marine cyclic peptides with antibacterial, antifungal, antiparasitic, or antiviral properties. These natural products were categorized according to their sources—sponges, mollusks, crustaceans, crabs, marine bacteria, and fungi—and chemical structure—cyclic peptides and depsipeptides. The antimicrobial activities, including against drug-resistant microorganisms, unusual structural characteristics, and hits more advanced in (pre)clinical studies, are highlighted. Nocathiacins I–III (91–93), unnarmicins A (114) and C (115), sclerotides A (160) and B (161), and plitidepsin (174) can be highlighted considering not only their high antimicrobial potency in vitro, but also for their promising in vivo results. Marine cyclic peptides are also interesting models for molecular modifications and/or total synthesis to obtain more potent compounds, with improved properties and in higher quantity. Solid-phase Fmoc- and Boc-protection chemistry is the major synthetic strategy to obtain marine cyclic peptides with antimicrobial properties, and key examples are presented guiding microbiologist and medicinal chemists to the discovery of new antimicrobial drug candidates from marine sources.

Absolute Stereochemistry Determination of Bioactive Marine-Derived Cyclopeptides by Liquid Chromatography Methods: An Update Review (2018–2022)

“…A number of marine-derived cyclopeptides exhibited a broad spectrum of antimicrobial activities, including bacteria, protozoa, fungi, and viruses [ 202 , 203 , 204 ]. Moreover, some of the marine cyclopeptides also showed antimicrobial activities towards several drug-resistant bacteria and fungi, making them a very promising source of novel antimicrobial agents to revert multidrug-resistance [ 203 ]. Among the 91 new marine-derived cyclopeptides isolated from 2018, 16 ( 44 – 59 ) were tested for their antimicrobial activity ( Figure 11 ) and showed promising results.…”

Therapeutic Potential of Marine Bioactive Peptides against Human Immunodeficiency Virus: Recent Evidence, Challenges, and Future Trends

“…Microspinosamide, a tridecadepsipeptide from the sponge Sidonops microspinosa, is another cyclic depsipeptide with an inhibitory effect against cytopathic action of HIV-1 infection in an in vitro XTT-based assay with an EC 50 value of 0.2 μg/mL [ 101 ]. Similarly, theopapuamide B, isolated from the bacteria symbiosis sponges Theonella swinhoei and S. mirabilis exhibited anti-HIV activity in an in vitro single-round HIV-1 infectivity assay against HIV-1 SF162 envelope pseudotyped viruses with an IC 50 value of 0.8 µg/mL [ 101 ]. Celebeside A from S. mirabilis has similarly been attributed with HIV-1 neutralization activity with an IC 50 value of 1.9 µg/mL in a single-round infectivity assay [ 101 ].…”

“…Similarly, theopapuamide B, isolated from the bacteria symbiosis sponges Theonella swinhoei and S. mirabilis exhibited anti-HIV activity in an in vitro single-round HIV-1 infectivity assay against HIV-1 SF162 envelope pseudotyped viruses with an IC 50 value of 0.8 µg/mL [ 101 ]. Celebeside A from S. mirabilis has similarly been attributed with HIV-1 neutralization activity with an IC 50 value of 1.9 µg/mL in a single-round infectivity assay [ 101 ].…”

Nα‐Methylation of arginine: Implications for cell‐penetrating peptides

“…This replacement of N–H with N–CH 3 eliminates the ability to donate a hydrogen bond to solvent water molecules and thereby reduces the energetic cost of desolvation that is necessary for crossing a lipid bilayer 20 . Many other natural cyclic peptides are likewise N ‐methylated on their main chain 21–23 …”