Recent Applications of Retro-Inverso Peptides

Abstract

Natural and de novo designed peptides are gaining an ever-growing interest as drugs against several diseases. Their use is however limited by the intrinsic low bioavailability and poor stability. To overcome these issues retro-inverso analogues have been investigated for decades as more stable surrogates of peptides composed of natural amino acids. Retro-inverso peptides possess reversed sequences and chirality compared to the parent molecules maintaining at the same time an identical array of side chains and in some cases similar structure. The inverted chirality renders them less prone to degradation by endogenous proteases conferring enhanced half-lives and an increased potential as new drugs. However, given their general incapability to adopt the 3D structure of the parent peptides their application should be careful evaluated and investigated case by case. Here, we review the application of retro-inverso peptides in anticancer therapies, in immunology, in neurodegenerative diseases, and as antimicrobials, analyzing pros and cons of this interesting subclass of molecules.

Disrupting GPCR Complexes with Smart Drug-like Peptides

“…Along similar lines, the so-called retro-enantio approach can likewise give rise to peptides fully resistant to natural proteases. In a retro-enantio peptide both amino acid sequence and residue chirality are reversed relative to the parent structure, but despite these substantial changes the orientation of the side chains is preserved, hence a resemblance in overall shape (Figure 2D), while the inverted chirality curbs protease degradation, enhancing half-life and thus the potential as a new drug lead [77]. Moreover, the retro-enantio analogue tends to be less immunogenic than the cognate sequence [78].…”

Examining Topoisomers of a Snake-Venom-Derived Peptide for Improved Antimicrobial and Antitumoral Properties

“…This still rather broad category may be further narrowed down to peptides such as those in this work, i.e., with fully inverted amino acid sequence (retro isomers) or with the canonic sequence made up of residues of reversed chirality (enantio isomers), or with both features combined (retroenantio isomers). Research in this area over recent years has unveiled rather interesting features of these isomers, particularly the retroenantio ones [ 23 , 24 , 25 , 26 , 27 ].…”

Antiseptic 9-Meric Peptide with Potency against Carbapenem-Resistant Acinetobacter baumannii Infection

“…Another intriguing method for producing peptidomimetics is the retro inversion (RI) strategy, which uses D-amino acids as stable surrogates for L-amino acids that are delivered in a reverse (retro) order to the original molecule. Due to their inverted chirality, these peptides are less susceptible to proteolytic digestion, resulting in a longer half-life [35,36]. Indeed, some of the RI analogues of AMPs in clinical trials are currently displaying good specificity against ESKAPE pathogens, such as RI-omiganan [37], RI-CAMEL [38], and RI-temporin A [39].…”