Table 16 - uploaded by Silvia Stotani
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Citations
... In this larger size regime (>500 MW), a majority of current macrocyclic drug candidates are natural products or close variants of natural products. 3 Relative to small molecules, there is less flexibility to guide the design of these noncanonical drug candidates to optimize both binding and bioavailability. Studies that further the understanding of macrocyclic peptides and their optimization against biological targets are therefore of great value. ...
... Peptide macrocyclization indeed increases the affinity and selectivity for a specific target, as well as the metabolic stability, permeability and pharmacokinetic properties [71,72]. The current pipeline of macrocycles includes over 80 approved drugs, with almost half of them belonging to the cyclic peptide class [72][73][74]. Among the well-known examples of cyclic peptide drugs on the market, eight currently target GPCRs. ...
The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
... 4 Among their clinical applications as drugs, macrocycles are used in oncology (temsirolimus and 5,6 epothilone B derivatives 7,8 ), as antibiotics (vancomycin, macrolides, and rifampicin), immunology (sirolimus and zotarolimus), and in dermatology (pimecrolimus). 9 Other applications of macrocycles are in supramolecular chemistry (crown ethers, 10 cryptands, catenanes, rotaxanes, 11 and calixarenes). Recently, macrocycles have received growing attention in medicinal chemistry 12−15 because of their unique ability to disrupt protein−protein interactions, 16 improve metabolic stability, 17 and improve cellular permeability by conformational restriction 18−21 resulting in a higher oral bioavailability compared to noncyclic congeners. ...
Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional “basic knowledge” alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.
... Folding through cyclisation helps to bury some peptide polarity in the interior of the macrocycle making its exterior surface less polar, more hydrophobic, and consequently more permeable through lipid membranes [193]. These and other advantages have led to approval of ~40 macrocyclic peptide drugs (Table VI), with many other macrocyclic peptides in clinical trials or in development [194,195]. Nevertheless, like almost all linear peptides, most cyclic peptides are not particularly membrane permeable; only a few are absorbed from the intestine, and even fewer have sufficient oral bioavailability to be effective by the oral route [193]. Here, we summarise examples of orally-administered cyclic peptides, as distinct from other macrocycles [196], and point to some observations on these and model cyclic peptides that may help lead to improvements in cyclic peptides as oral drugs. ...
... Cyclic peptide drugs have been approved for clinical use in a number of disease settings [195,197,198] (Table VI), with bacterial and fungal infections, diabetes, and cancer being most common [193,194,[197][198][199]. Most cyclic peptide drugs are delivered by injection, with very few used orally due to the issues raised in this review (Fig. 6). ...
... Selected cyclic peptides that have progressed to clinical trials or are in development are shown in Table VII [194,195,218]. Most have only low oral bioavailability due to high polarity, flexibility, or charged amines/carboxylates that all promote solvation by water. ...
In its 33 years, ADDR has published regularly on the potential of oral delivery of biologics especially peptides and proteins. In the intervening period, analysis of the preclinical and clinical trial failures of many purported platform technologies has led to reflection on the true status of the field and reigning in of expectations. Oral formulations of semaglutide, octreotide, and salmon calcitonin have completed Phase III trials, with oral semaglutide being approved by the FDA in 2019. The progress made with oral peptide formulations based on traditional permeation enhancers is against a background of low oral and variable bioavailability values of ~1%, leading to a current perception that only potent peptides with a viable cost of synthesis can be realistically considered. Desirable features of candidates should include a large therapeutic index, some stability in the GI tract, a long elimination half-life, and a relatively low clearance rate. Administration in nanoparticle formats have largely disappointed, with few prototypes reaching clinical trials: insufficient particle loading, lack of controlled release, low epithelial particle uptake, and lack of scalable synthesis are being the main reasons for discontinuation. Disruptive technologies based on engineered devices promise improvements, but scale-up and toxicology aspects are issues to address. In parallel, medicinal chemists are synthesizing stable hydrophobic macrocyclic candidate peptides of lower molecular weight with potential for greater oral bioavailability than linear peptides, but without a requirement for elaborate drug delivery systems. In summary, while there have been advances in understanding the limitations of peptides for oral delivery, low membrane permeability, metabolism, and high clearance rates continue to hamper progress.
RNA molecules both contribute to and are causative of many human diseases. One method to perturb RNA function is to target its structure with small molecules. However, discovering bioactive ligands for RNA targets is challenging. Here, we show that the bioactivity of a linear dimeric ligand that inactivates the RNA trinucleotide repeat expansion that causes myotonic dystrophy type 1 [DM1; r(CUG)exp] can be improved by macrocyclization. Indeed, the macrocyclic compound is ten times more potent than the linear compound for improving DM1‐associated defects in cells, including in patient‐derived myotubes (muscle cells). This enhancement in potency is due to the macrocycle's increased affinity and selectively for the target, which inhibit r(CUG)exp’s toxic interaction with muscleblind‐like 1 (MBNL1), and its superior cell permeability. Macrocyclization could prove to be an effective way to enhance the bioactivity of modularly assembled ligands targeting RNA.
