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.
Highlights
These results showed that the Dox-loaded micelles functionalized with the RI-VS analogue had better anti-glioma effects in vivo, with fewer side effects compared with other formulations
According with preliminary studies using molecular modeling and docking, the proposed RI peptide was expected to bind to the angiotensin converting enzyme type 2 (ACE2) which is the target of SARS-CoV in lung cells, and to work as an inhibitor able to prevent the proteolysis required for activation of the S spike protein [104]
Aβ1–40/42 levels decreased in plasma and brain, diminishing the levels of soluble amyloid-β protein precursor (AβPP) production and of insoluble Aβ following chronic treatments. These results suggested a possible use of the chimeric RI peptides as a selective disease-modifying therapy for Alzheimer’s disease (AD) [109]
Summary
In the cure of cancer, side effects following conventional drug treatments are currently on the rise. Liu et al [51] reported the in vitro investigation of several linear RI peptides based on the RGD motif conjugated to cell-penetrating peptides based on poly-arginines Their results suggested that linear RI analogues were potentially useful as tumor targeting carriers with biological activity similar to RGD alone. The RI variant of VS conjugated with PEG-PLA (poly-lactic acid) was used to prepare micelles which efficiently encapsulated doxorubicin (DOX), penetrated the tumor mass, and reduced its volume more efficiently compared to the control, the free drug, or other micelle formulations These results showed that the Dox-loaded micelles functionalized with the RI-VS analogue had better anti-glioma effects in vivo, with fewer side effects compared with other formulations. TfR-targeting T7 peptide (Table 1) was shown to have enhanced serum stability and higher binding affinity to TfR [60] than the parent peptide This property was efficiently exploited modifying the surface of liposomes (LIP) to realize a tumor selective drug delivery system. A complete pharmacokinetic study was performed to further investigate the potential of RI-T7-LIP in vivo using Docetaxel-loaded RI-T7-LIP which induced markedly increased apoptotic and necrotic areas in the treated mouse models
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