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Some selected small organic drug molecules-peptide conjugates examples. (A) paclitaxel (antitumor) conjugate (CAS RN: 1293910-28-7) (6), (B) salicylanilide-derivative (antimycobacterial) conjugate (CAS RN 2100270-47-9) (8), (C) acyclovir (antiviral, HSV-1 and 2) conjugate (CAS RN 1520867-23-5) (9), (D) coumarin derivative (antifungal) conjugate (CAS RN: 1644441-61-1) (10), (E) cinnamic acid/4-aminoquinoline (antimalarial, dual action) conjugate (CAS RN 1392506-21-6) (11), (F) ibuprofen (cancer targeting NSAID) conjugate (CAS RN 2375589-19-6) (12).
Source publication
Peptide–drug conjugates are organic molecules composed of (i) a small drug molecule, (ii) a peptide and (iii) a linker. The drug molecule is mandatory for the biological action, however, its efficacy can be enhanced by targeted delivery, which often also reduces unwanted side effects. For site-specificity the peptide part is mainly responsible. The...
Contexts in source publication
Context 1
... several cases, cell penetrating peptides are employed, which can facilitate the appropriate translocation of the anticancer agent across the cell membrane to its desired place of application. Selected examples for drug conjugates in this field are as follows: doxorubicin (Dox), daunorubicin (Dau), methotrexate (Mtx) (4,5) and paclitaxel (taxol) (6) too ( Figure 1A). Besides improved pharmacological properties, peptide-drug conjugates can also be used in a similar way in diagnostic applications, e.g. for cancer imaging. ...
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... further important field of application is antimicrobial utilisation. Some conjugates were tested on various multiresistant bacteria (8) (Figure 1B), and others were designed to act on viruses (9) ( Figure 1C). For this purpose heterocycles and macrocyclic systems were used. ...
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... further important field of application is antimicrobial utilisation. Some conjugates were tested on various multiresistant bacteria (8) (Figure 1B), and others were designed to act on viruses (9) ( Figure 1C). For this purpose heterocycles and macrocyclic systems were used. ...
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... this purpose heterocycles and macrocyclic systems were used. Examples with antifungal applications are also known (10) ( Figure 1D). Additionally, some conjugates were designed to treat malaria utilising quinoline derivative as antimalarial agent (11) ( Figure 1E). ...
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... with antifungal applications are also known (10) ( Figure 1D). Additionally, some conjugates were designed to treat malaria utilising quinoline derivative as antimalarial agent (11) ( Figure 1E). ...
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... peptidedrug conjugates were created too. Importantly, by the application of polyanionic peptides, anti-inflammatory drugs were effectively delivered into bones or other types of tumor cells (12) ( Figure 1F). Furthermore, osteoarthritis can be treated by some conjugates including methotrexate (13). ...
Citations
... Nonetheless, addressing these issues is possible through the structural modification of peptides and the exploration of innovative structural motifs that enhance both stability and circulation time [171]. Mándity and coworkers have created a database of PDCs (ConjuPepBD) that encompasses over 1600 conjugates documented in approximately 230 publications [172]. Lutathera and Pepaxto stand as the sole FDA-approved peptide drug conjugates (PDCs) [173]. ...
Simple Summary
The extraordinary growth in the global pharmaceutical industry has extended to include peptides, which are amino acids linked together with an amide bond. Due to their well-tolerable safety profile and specificity, therapeutic peptides offer a means to address unmet medical challenges. A well-known example of a commonly administered peptide is insulin. Peptides are considered excellent complements and, in some cases, preferable alternatives to both small molecules such as paracetamol and very large antibodies. At present, around 100 peptide drugs are available on the global market, with ongoing research yielding over 150 peptides in clinical development and an additional 400–600 peptides undergoing preclinical studies. Peptides play a crucial role in cancer research and treatment, and they can be involved in various aspects of cancer development, detection, and treatment. These medicines demonstrate exceptional efficacy in combating cancer, contributing to improved survival rates for cancer patients.
Abstract
The United States Food and Drug Administration (FDA) has approved a plethora of peptide-based drugs as effective drugs in cancer therapy. Peptides possess high specificity, permeability, target engagement, and a tolerable safety profile. They exhibit selective binding with cell surface receptors and proteins, functioning as agonists or antagonists. They also serve as imaging agents for diagnostic applications or can serve a dual-purpose as both diagnostic and therapeutic (theragnostic) agents. Therefore, they have been exploited in various forms, including linkers, peptide conjugates, and payloads. In this review, the FDA-approved prostate-specific membrane antigen (PSMA) peptide antagonists, peptide receptor radionuclide therapy (PRRT), somatostatin analogs, antibody–drug conjugates (ADCs), gonadotropin-releasing hormone (GnRH) analogs, and other peptide-based anticancer drugs are analyzed in terms of their chemical structures and properties, therapeutic targets and mechanisms of action, development journey, administration routes, and side effects.
... Conjugation can be formed by either the terminals of the peptide or through a side chain with the application of an appropriate functional group. A linker is frequently used in order to increase the distance between the peptide and the active ingredient or providing reversibility (capability of detachment under appropriate conditions) [9][10][11][12][13]. CPPs also can be the component of more complex drug delivery systems combined with polymers, dendrimers, or antibodies for targeting, especially in cancer therapy [14,15]. ...
Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates. We have selected three CPPs with a linear backbone, including penetratin, a naturally occurring oligopeptide; two of its modified sequence analogues (6,14-Phe-penetratin and dodeca-penetratin); and three natural CPPs with a cyclic backbone: Kalata B1, the Sunflower trypsin inhibitor 1 (SFT1), and Momordica cochinchinensis trypsin inhibitor II (MCoTI-II). We have also built conjugates with the small-molecule drug compounds doxorubicin, zidovudine, and rasagiline for each peptide. Molecular dynamics (MD) simulations were carried out with explicit membrane models. The analysis of the trajectories showed that the interaction of penetratin with the membrane led to spectacular rearrangements in the secondary structure of the peptide, while cyclic peptides remained unchanged due to their high conformational stability. Membrane–peptide and membrane–conjugate interactions have been identified and compared. Taking into account well-known examples from the literature, our simulations demonstrated the utility of computational methods for CPP complexes, and they may contribute to a better understanding of the mechanism of penetration, which could serve as the basis for delivering conjugated drug molecules to their intracellular targets.
... Notably, ConjuPepDB, a database of peptide-drug conjugates, has been recently released. It covers more than 1600 peptide-conjugated drug molecules, along with basic information about their biomedical application and the type of chemical conjugation employed [75]. ...
Cell-penetrating peptides (CPPs), developed for more than 30 years, are still being extensively studied due to their excellent delivery performance. Compared with other delivery vehicles, CPPs hold promise for delivering different types of drugs. Here, we review the development process of CPPs and summarize the composition and classification of the CPP-based delivery systems, cellular uptake mechanisms, influencing factors, and biological barriers. We also summarize the optimization routes of CPP-based macromolecular drug delivery from stability and targeting perspectives. Strategies for enhanced endosomal escape, which prolong its half-life in blood, improve targeting efficiency and stimuli-responsive design and are comprehensively summarized for CPP-based macromolecule delivery. Finally, after concluding the clinical trials of CPP-based drug delivery systems, we extracted the necessary conditions for a successful CPP-based delivery system. This review provides the latest framework for the CPP-based delivery of macromolecular drugs and summarizes the optimized strategies to improve delivery efficiency.
... Databases annotating modified amino acid residues in proteins have recently been established as well [6][7][8]. Modifications of amino acid residues are also considered in records of peptide sequences in various databases [9][10][11][12][13][14][15][16][17][18] and during prediction of both structure [19] and physicochemical properties of peptides such as, for example, the isoelectric point [20]. There are datasets of non-proteinogenic and modified amino acids, such as the SwissSideChain database [21] and Norine list of monomers [14]. ...
... Several databases of bioactive peptides, containing components other than proteinogenic amino acids, have been recently launched [9][10][11][12][13][14][15][16][17][18]. In comparison with them, BIOPEP-UWM possesses both strong points and limitations. ...
Bovine casein is one of the most known precursors of bioactive peptides among food proteins. Thus far in silico investigations addressing casein took no account of the impact of modifications of amino acid residues on the feasibility of bioactive peptide release. The present study aimed to determine the effect of such modification on the possibility of release of bioactive peptides from casein during simulated digestion. The αs1-, αs2-, β-, and κ-casein sequences were deposited in the BIOPEP-UWM protein database considering phosphorylated amino acids, cysteine residues forming disulfide bridges, and pyroglutamic acid residues. The frequency of occurrence of bio-active fragments and the frequency of their release by digestive enzymes were determined for the analyzed modified and unmodified proteins. Peptides found exclusively in the sequences of unmodified proteins were deemed as false-positive results. From 1.74% (β-casein A2) to 4.41% (αs2-casein B and D) of the false-positive results were obtained for the total frequency of occur-rence of bioactive fragments (sums of frequencies computed for all activities). In turn, from 1.78% (κ-casein B) to 9.18% (β-casein A2 and A3) of false-positive results were obtained for the predicted total frequency of release of bioactive peptides by the system of digestive enzymes (pepsin, trypsin, and chymotrypsin).
... Peptide-drug conjugates (PDCs) are a type of targeted therapeutic in which a peptide is covalently bonded to a small organic drug molecule. PDC is usually made up of three parts: a homing peptide, a linker, and a payload [154,155]. The functional groups in the linker region determine different types of drug release and can be classified into four different classes: enzyme-cleavable (ester, amide, and carbamate), acid-cleavable (hydrazone and carbonate), reducible disulfide, and non-cleavable (thioether, oxime, and triazole). ...
Peptides can act as targeting molecules, analogously to oligonucleotide aptamers and antibodies. They are particularly efficient in terms of production and stability in physiological environments; in recent years, they have been increasingly studied as targeting agents for several diseases, from tumors to central nervous system disorders, also thanks to the ability of some of them to cross the blood–brain barrier. In this review, we will describe the techniques employed for their experimental and in silico design, as well as their possible applications. We will also discuss advancements in their formulation and chemical modifications that make them even more stable and effective. Finally, we will discuss how their use could effectively help to overcome various physiological problems and improve existing treatments.
... The peptide moiety can be the active ingredient, but it can also be a carrier or a stabilising agent. 16,24,25 Recently, the use of peptide conjugates has increased, with particular attention on pharmaceutical applications, as demonstrated by ConjuPepDB, a database of peptidedrug conjugates, recently published by Balogh et al. 26,27 In most cases, the peptide is not mandatory for the activity, but it enhances the overall efficacy, for example, by additional binding specificity. 25,28,29 Various chemical linkages are used to perform the conjugation, the most frequently utilised are amide, sulphonamide, disulphide, glucuronide, carbamate, ether, and ester bonds. ...
... 25,28,29 Various chemical linkages are used to perform the conjugation, the most frequently utilised are amide, sulphonamide, disulphide, glucuronide, carbamate, ether, and ester bonds. 26,28 It was reported that tripeptides conjugated with a small organic molecule, i.e. kojic acid, 30,31 mimosine, 32 kaffeic acid, 33 are more potent tyrosinase inhibitors than the original organic molecule or the tripeptide alone. For both conjugates, the amino acid sequences in kojic acid-tripeptide 30 and mimosine-tripeptide 32 of the most effective tripeptides were consistent. ...
... Conjugation of peptides with small organic molecules has been recently widely applied, mainly for their application as carriers or stabilising agents. [25][26][27] An interesting example is represented by the use of various peptides and their conjugates as cosmeceutical active ingredients, described in recent reviews 15, . 16 In this work, we report the synthesis of nine conjugates of three thiosemicarbazones with designed tripeptides, based on the Phe-Xaa-Tyr motif, where Xaa ¼ Phe, Trp, or Tyr. ...
The development of skin-care products is recently growing. Cosmetic formulas containing active ingredients with proven efficacy, namely cosmeceuticals, are based on various compounds, including peptides. Different whitening agents featuring anti-tyrosinase activity have been applied in the cosmeceutical field. Despite their availability, their applicability is often limited due to several drawbacks including toxicity, lack of stability, and other factors. In this work, we present the inhibitory effect on diphenolase activity of thiosemicarbazone (TSC)-peptide conjugates. Tripeptides FFY, FWY, and FYY were conjugated with three TSCs bearing one or two aromatic rings via amide bond formation in a solid phase. Compounds were then examined as tyrosinase and melanogenesis inhibitors in murine melanoma B16F0 cell line, followed by the cytotoxicity assays of these cells. In silico investigations explained the differences in the activity, observed among tested compounds. Mushroom tyrosinase was inhibited by TSC1-conjugates at micromolar level, with IC50 lower than this for kojic acid, a widely used reference compound. Up to now, this is the first report regarding thiosemicarbazones conjugated with tripeptides, synthesised for the purpose of tyrosinase inhibition.
... The report also highlights the dominance of therapeutic segment of PDC market with the revenue share of 82.3% in 2021. ConjuPepBD, a freely available database of peptide drug conjugates lists out more than 1600 conjugates for various biomedical applications (Balogh et al. 2021). Unlike most of the pre-clinical or clinical studies utilizing PDCs in anti-cancer therapy, very few pre-clinical studies have mentioned the use of ocular targeting conjugates probably due to the limited therapeutic research in the area of ocular disease management owing to the physiological as well as anatomical complexity of the eye. ...
Effective delivery of drug molecules to the target site is a challenging task. In the last decade, several innovations in the drug delivery system (DDS) have tremendously improved the therapeutic efficacy of drug molecules. Among various DDS, cell-penetrating peptides (CPPs) based DDS have gathered notable attention owing to their safety, efficacy, selectivity, specificity, and ease of synthesis. CPPs are emerging as an efficient and effective pharmaceutical nanocarriers-based platforms for successful management of various important human health disorders. Failure of several current chemotherapeutic strategies is attributed to low solubility, reduced bioavailability, and off-target delivery of several anti-cancer drugs. Similarly, development of therapeutics for vision-threatening disorders is challenged by the anatomical as well as physiological complexity of the eye. Such therapeutic challenges in cancer and ocular disease management can be overcome by developing cell-penetrating peptide (CPP) based peptide drug conjugates (PDCs). CPPs can be used to deliver various types of cargo molecules including nucleic acids, small molecules, and peptides/proteinaceous agents. In this review, we have briefly introduced CPPs and the linker strategies employed for the development of PDCs. Furthermore, recent studies employing CPP-based PDCs for cancer and ocular disease management have been discussed in detail highlighting their significance over conventional DDS. Later sections of the review are focused on the current status of clinical trials and future implications of CPP-based PDCs in vaccine development.
Key points
• Cell-penetrating peptides (CPPs) can deliver a variety of cargo macromolecules via covalent and non-covalent conjugation.
• CPP-based peptide drug conjugates (PDCs) can overcome drawbacks of conventional drug delivery methods such as biocompatibility, solubility, stability, and specificity.
• Various PDCs are in clinical trial phase for cancer and ocular therapeutics.
... This attribute enables the targeted delivery of the cytotoxic payload. 8 The targeting peptide used in the conjugates must be highly specic and lead to receptor-mediated endocytosis of the PDC by the target cells only. The highly toxic payloads, for instance, maytansine, camptothecin derivatives, auristatin, or doxorubicin are recommended to choose in the conjugates. ...
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.
... Still, it may also be biodegradable to provide a regulated release. [57] Targeting particular cells improves the therapeutic efficiency of conjugated medicines while decreasing their adverse effects. However, since peptides are comprised of short amino acid sequences, it is impossible to attach large quantities of medications to peptide molecules. ...
Neuroendocrine tumors (NET) form in the body's neuroendocrine system and are considered malignant; it takes years for most NETs to evolve, but not all. NETs are predominantly located in the lungs and the gastrointestinal tract; NETs in the lungs are carcinoid tumors. Treating these tumors is challenging, and therapeutic strategies have become priorities for researchers and clinicians. A neuroendocrine lung tumor is one such tumor that is very difficult to treat. To manage hormonal disorders caused by neuroendocrine tumors, somatostatin analogs are the gold standard. New data suggests that somatostatin analogs can be antiproliferative treatments for neuroendocrine tumors. Despite their apparent clinical interchangeability, comparative noninferiority studies between octreotide and lanreotide have not been conducted. Thus, it is where we look at different drug conjugates which act on the tumor. Radioligand, for example, is a promising model for Peptide Somatostatin receptors, typically more expressed on the surface of metastatic lung NETs.Consequently, a radioligand-based drug-peptide delivery is a particular target delivery method. Another type of drug conjugate is the novel technology named Peptide-drug conjugate (PDC) has made slow and steady progress in this treatment. PDC has the advantage of covalently altering a ligand peptide, which can target the specific cell surface receptors or biomarkers at the tumor site, exert a long-lasting function, and extend the effect of time, resulting in an overall desirable pharmacokinetic profile as a means of delivering anticancer drugs. Therefore, this review will summarize the recent technologies and anticancer agents that PDC used for the therapeutic efficiency and the intracellular uptake efficiency of active ingredients and receptors expressed on LU-NETs cells.
... 11,80,81 The scale of use of peptide conjugates, particularly for pharmaceutical applications, has increased to such an extent that in 2020 Balogh et al. introduced ConjuPepDB: a database of peptide-drug conjugates. 82,83 It summarizes up-to-now described organic molecules consisting of a small drug molecule, a linker, and a peptide (Figure 3). Figure 3. An example of the structure of peptide conjugate, including the lysine linker. ...
... 96 ester. 82,84 Of special note is the use of the copper(I)-catalyzed alkyne-azide 1,3-dipolar Huisgen's cycloaddition, also known as click reaction, 98-101 that has been applied to the synthesis of a large variety of peptide-conjugates 102,103 as well as for the preparation of conformationally constrained peptides via side chain to side chain cyclization. [104][105][106] The purpose of the conjugation applied for the compounds included in this thesis was to evaluate: ...
Cosmeceuticals, i.e., cosmetic products with active ingredients possessing the scientifically proven and thoroughly evaluated biological activity, are becoming progressively more common on the market. Consumer awareness has prompted manufacturers to create formulas with a valuable composition, good permeability through the skin, and prolonged stability. Peptides, short chains of amino acids, are good candidates for active ingredients. Due to the ease of their modification, uncomplicated synthesis, and the possibility of giving them the desired properties, they are becoming frequent ingredients in cosmeceuticals. This doctoral dissertation discusses two enzymes contributing to the appearance of signs of skin aging – elastase, responsible for the breakdown of collagen fibers, and tyrosinase – directly affecting the synthesis of melanin and skin discoloration. Design, synthesis, biological investigation, and molecular modeling of peptides and their conjugates with small organic molecules were discussed. In vitro studies of these compounds indicated inhibitors of the abovementioned enzymes, some of them with micromolar activity. The correlation between the structure of obtained compounds and their activity was discussed, and special attention was paid to the role of peptide conjugates in the design of biologically active compounds.
