In the design and development of therapeutic agents, macromolecules with restricted structures have stronger competitive edges than linear biological entities since cyclization can overcome the limitations of linear structures. The common issues of linear peptides include susceptibility to degradation of the peptidase enzyme, off-target effects, and necessity of routine dosing, leading to instability and ineffectiveness. The unique conformational constraint of cyclic peptides provides a larger surface area to interact with the target at the same time, improving the membrane permeability and in vivo stability compared to their linear counterparts. Currently, cyclic peptides have been reported to possess various activities, such as antifungal, antiviral and antimicrobial activities. To date, there is emerging interest in cyclic peptide therapeutics, and increasing numbers of clinically approved cyclic peptide drugs are available on the market. In this review, the medical significance of cyclic peptides in the defence against viral infections will be highlighted. Except for chikungunya virus, which lacks specific antiviral treatment, all the viral diseases targeted in this review are those with effective treatments yet with certain limitations to date. Thus, strategies and approaches to optimise the antiviral effect of cyclic peptides will be discussed along with their respective outcomes. Apart from isolated naturally occurring cyclic peptides, chemically synthesized or modified cyclic peptides with antiviral activities targeting coronavirus, herpes simplex viruses, human immunodeficiency virus, Ebola virus, influenza virus, dengue virus, five main hepatitis viruses, termed as type A, B, C, D and E and chikungunya virus will be reviewed herein.
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