Converting peptides into drugs targeting intracellular protein–protein interactions

Philippe, Grégoire J.B.; Craik, David J.; Henriques, Sónia Troeira

doi:10.1016/j.drudis.2021.01.022

Cited by 65 publications

(89 citation statements)

References 130 publications

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“…Proteolytic stability and various toxicities of these peptides are challenging to overcome in terms of drug development. One strategy frequently used is cyclization, which can be established in various ways, for example, by introduction of cysteine bridges, head-to-tail cyclization, and other chemical modifications, such as lactam, hydrocarbon, or triazole bridges [46]. The introduction or natural occurrence of disulfide bonds can stabilize the active conformation of a peptide by reducing the energy cost required to bind target interfaces and increasing the affinity of the peptide to bind to and modulate them.…”

Section: Discussionmentioning

confidence: 99%

Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

et al. 2021

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According to the World Health Organization (WHO) the development of resistance against antibiotics by microbes is one of the most pressing health concerns. The situation will intensify since only a few pharmacological companies are currently developing novel antimicrobial compounds. Discovery and development of novel antimicrobial compounds with new modes of action are urgently needed. Antimicrobial peptides (AMPs) are known to be able to kill multidrug-resistant bacteria and, therefore, of interest to be developed into antimicrobial drugs. Proteolytic stability and toxicities of these peptides are challenges to overcome, and one strategy frequently used to address stability is cyclization. Here we introduced a disulfide-bond to cyclize a potent and nontoxic 9mer peptide and, in addition, as a proof-of-concept study, grafted this peptide into loop 6 of the cyclotide MCoTI-II. This is the first time an antimicrobial peptide has been successfully grafted onto the cyclotide scaffold. The disulfide-cyclized and grafted cyclotide showed moderate activity in broth and strong activity in 1/5 broth against clinically relevant resistant pathogens. The linear peptide showed superior activity in both conditions. The half-life time in 100% human serum was determined, for the linear peptide, to be 13 min, for the simple disulfide-cyclized peptide, 9 min, and, for the grafted cyclotide 7 h 15 min. The addition of 10% human serum led to a loss of antimicrobial activity for the different organisms, ranging from 1 to >8-fold for the cyclotide. For the disulfide-cyclized version and the linear version, activity also dropped to different degrees, 2 to 18-fold, and 1 to 30-fold respectively. Despite the massive difference in stability, the linear peptide still showed superior antimicrobial activity. The cyclotide and the disulfide-cyclized version demonstrated a slower bactericidal effect than the linear version. All three peptides were stable at high and low pH, and had very low hemolytic and cytotoxic activity.

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Section: Discussionmentioning

confidence: 99%

Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

et al. 2021

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“…The design principles of interface peptides and the repertoire of technical solutions are detailed in recent reviews [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Optimization of the linear peptides is usually required to increase the binding affinity to the target protein, overcome a number of pharmacodynamic (pharmacokinetic) limitations and unfavorable physicochemical properties that reduce the in vivo efficacy.…”

Section: Current Approaches To the Design Of Interfacial Peptidesmentioning

confidence: 99%

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

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“…More liver lesions were detected; thus, [ 18 F]AlF-NOTA-octreotide is promising to replace the 68 Ga-labeled PET tracer [78]. 90 Y-DOTATOC, currently in a Phase II clinical trial, has been studied for peptide receptor radionuclide therapy (PRRT) since 1997 [79]. The renal absorption dose was reduced by 27% on average and showed no effect on tumor uptake, but was found to cause metabolic acidosis producing side effects such as nausea [80].…”

Section: Targeting Integrinsmentioning

confidence: 99%

“…Second, the short biological half-life of peptides results in a limited distribution and targeting time for peptide-drug conjugates in vivo, leaving a limited period for the payload to enter tumor cells before the tumor-targeting peptide's degradation. At present, there are many methods to extend the biological half-life of peptides, including head-to-tail cyclization, disulfide bond cyclization, replacement of unnatural amino acids, peptidomimetics, stapled peptides, and the bicycle strategy [90]. It should be noted that these methods cannot reduce the effect of the binding of tumor-targeting peptides to receptors [91] (see Outstanding questions).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Zhu

Tang

2021

Trends in Pharmacological Sciences

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Drug delivery systems are generally believed to comprise drugs and excipients. A peptide-drug conjugate is a single molecule that can simultaneously play multiple roles in a drug delivery system, such as in vivo drug distribution, targeted release, and bioactivity functions. This molecule can be regarded as an integrated drug delivery system, so it is called a molecular drug delivery system. In the context of cancer therapy, a peptide-drug conjugate comprises a tumor-targeting peptide, a payload, and a linker. Tumor-targeting peptides specifically identify membrane receptors on tumor cells, improve drug-targeted therapeutic effects, and reduce toxic and side effects. Payloads with bioactive functions connect to tumor-targeting peptides through linkers. In this review, we explored ongoing clinical work on peptide-drug conjugates targeting various receptors. We discuss the binding mechanisms of tumor-targeting peptides and related receptors, as well as the limiting factors for peptide-drug conjugate-based molecular drug delivery systems. Towards enhanced targeting on tumorsDespite the rapid development of anticancer drugs in the past few decades, cancer is one of the leading causes of death in the world [1]. Due to the lack of an effective means to distinguish tumor cells from normal cells [2], the accumulation efficiency of anticancer drugs in tumor cells is low and the toxic side effects on normal tissues are high. In the treatment process, drug resistance problems are caused by tumor heterogeneity [3], drug inactivation, transport, and metabolism, changes in drug targets, and tumor microenvironment dysfunction [4]. Although advanced drug delivery methods can partially solve problems of targeting, toxicity, and drug resistance [5], difficult industrialization, complicated process control, and huge costs remain insurmountable obstacles.Peptide-drug conjugates are emerging molecular drug delivery system (see Glossary) that achieve precise drug delivery and tumor-targeted release at the molecular level [6]. Current drug delivery systems, such as nano-drug delivery systems, use various complex excipients to assemble nanoscale particles that encapsulate drugs to be passively or actively delivered to target organs. The anticancer efficacy of nano-drug delivery systems is improved by an enhanced permeability retention effect to increase drug accumulation in tumors and the toxicity of nanodrug delivery systems is reduced by the long systemic circulation to decrease drug accumulation in normal organs [7]. However, a reappraisal of nano-drug delivery system design is suggested to improve their clinical efficacy and safety in cancer patients [8].By contrast, molecular drug delivery systems use a single peptide-drug conjugate molecule to achieve in vivo drug delivery, targeted drug release, and bioactivity, which can maximize the targeting effect and reduce drug resistance. Peptide-drug conjugates, which were first reported in 1972 by Freer et al.[9] (Box 1), are similar to the tethering of ligand-targeted drugs [10],

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Converting peptides into drugs targeting intracellular protein–protein interactions

Cited by 65 publications

References 130 publications

Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

Comparison of a Short Linear Antimicrobial Peptide with Its Disulfide-Cyclized and Cyclotide-Grafted Variants against Clinically Relevant Pathogens

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

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