Peptide-Based Drugs for Cancer Therapies

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (10 May 2023) | Viewed by 26162

Special Issue Editors


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Guest Editor
School of Biological Sciences, Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland 1010, New Zealand
Interests: antibody-drug conjugates; bioconjugate chemistry; peptide therapeutics; cancer targeted therapy; peptide chemistry
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Guest Editor
Department of Obstetrics & Gynaecology, School of Medicine, University of Otago, Christchurch 8140, New Zealand
Interests: targeted therapy; antibody-drug conjugates; precision medicine

Special Issue Information

Dear Colleagues,

Occupying the sweet middle space between small organic molecules and large proteins, peptides have demonstrated several unique advantages as potential drug candidates, including low toxicity, low immunogenicity, high potency and specificity. Moreover, technological developments toward peptide synthesis have improved the feasibility of peptide drug development. Thus, peptide therapeutics represent strong candidates for the growth and innovation of the future pharmaceutical world. In fact, the estimated global revenue of peptide therapeutics is expected to reach USD 50.60 billion by the year 2026. The latest survey of peptide-based drugs shows that more than 80 peptide-based drugs have been approved on the global market up until 2021, with another 155 peptides in various stages of clinical development and 400–600 more in preclinical stages. Notably, employing peptides in cancer treatment and management is one of the most topical directions in drug development. The aim of this Special Issue on “Peptide-Based Drugs for Cancer Therapies” is to emphasize current research efforts towards the development of novel peptide-based therapeutics for oncology.

Dr. Iman Kavianinia
Dr. Makhdoom Sarwar
Guest Editors

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Keywords

  • peptide-based anticancer drugs
  • peptide nanotherapeutics
  • peptide–drug conjugates
  • peptide drug design
  • peptide-based vaccines
  • immunosuppressive peptides
  • immune-stimulating peptides

Published Papers (9 papers)

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Research

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16 pages, 4094 KiB  
Article
The Anti-Tubercular Aminolipopeptide Trichoderin A Displays Selective Toxicity against Human Pancreatic Ductal Adenocarcinoma Cells Cultured under Glucose Starvation
by Johanes K. Kasim, Jiwon Hong, Anthony J. R. Hickey, Anthony R. J. Phillips, John A. Windsor, Paul W. R. Harris, Margaret A. Brimble and Iman Kavianinia
Pharmaceutics 2023, 15(1), 287; https://doi.org/10.3390/pharmaceutics15010287 - 14 Jan 2023
Viewed by 1491
Abstract
Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we [...] Read more.
Pancreatic ductal adenocarcinoma remains a highly debilitating condition with no effective disease-modifying interventions. In our search for natural products with promising anticancer activity, we identified the aminolipopeptide trichoderin A as a potential candidate. While it was initially isolated as an antitubercular peptide, we provide evidence that it is also selectively toxic against BxPC-3 and PANC-1 human pancreatic ductal adenocarcinoma cells cultured under glucose deprivation. This has critical implications for the pancreatic ductal adenocarcinoma, which is characterized by nutrient deprivation due to its hypovascularized network. We have also successfully simplified the trichoderin A peptide backbone, allowing greater accessibility to the peptide for further biological testing. In addition, we also conducted a preliminary investigation into the role of peptide lipidation at the N-terminus. This showed that analogues with longer fatty acyl chains exhibited superior cytotoxicity than those with shorter acyl chains. Further structural optimization of trichoderin A is anticipated to improve its biological activity, whilst ongoing mechanistic studies to elucidate its intracellular mechanism of action are conducted in parallel. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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16 pages, 2749 KiB  
Article
Palmitic Acid-Conjugated Radiopharmaceutical for Integrin αvβ3-Targeted Radionuclide Therapy
by Guangjie Yang, Hannan Gao, Chuangwei Luo, Xiaoyu Zhao, Qi Luo, Jiyun Shi and Fan Wang
Pharmaceutics 2022, 14(7), 1327; https://doi.org/10.3390/pharmaceutics14071327 - 23 Jun 2022
Cited by 4 | Viewed by 2086
Abstract
Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD2) has excellent targeting specificity for a variety of integrin αvβ3vβ5-positive tumors [...] Read more.
Peptide receptor radionuclide therapy (PRRT) is an emerging approach for patients with unresectable or metastatic tumors. Our previously optimized RGD peptide (3PRGD2) has excellent targeting specificity for a variety of integrin αvβ3vβ5-positive tumors and has been labeled with the therapeutic radionuclide [177Lu]LuCl3 for targeted radiotherapy of tumors. However, the rapid clearance of [177Lu]Lu-DOTA-3PRGD2 (177Lu-3PRGD2) in vivo requires two doses of 111 MBq/3 mCi to achieve effective tumor suppression, limiting its further clinical application. Albumin binders have been attached to drugs to facilitate binding to albumin in vivo to prolong the drug half-life in plasma and obtain long-term effects. In this study, we modified 3PRGD2 with albumin-binding palmitic acid (Palm-3PRGD2) and then radiolabeled Palm-3PRGD2 with 177Lu. [177Lu]Lu-DOTA-Palm-3PRGD2 (177Lu-Palm-3PRGD2) retained a specific binding affinity for integrin αvβ3vβ5, with an IC50 value of 5.13 ± 1.16 nM. Compared with 177Lu-3PRGD2, the 177Lu-Palm-3PRGD2 circulation time in blood was more than 6 times longer (slow half-life: 73.42 min versus 11.81 min), and the tumor uptake increased more than fivefold (21.34 ± 4.65 %IA/g and 4.11 ± 0.70 %IA/g at 12 h post-injection). Thus, the significant increase in tumor uptake and tumor retention resulted in enhanced efficacy of targeted radiotherapy, and tumor growth was completely inhibited by a single and relatively lowdose of 18.5 MBq/0.5 mCi. Thus, 177Lu-Palm-3PRGD2 shows great potential for clinical application. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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22 pages, 4189 KiB  
Article
The Influence of Short Motifs on the Anticancer Activity of HB43 Peptide
by Claudia Herrera-León, Francisco Ramos-Martín, Hassan El Btaouri, Viviane Antonietti, Pascal Sonnet, Laurent Martiny, Fabrizia Zevolini, Chiara Falciani, Catherine Sarazin and Nicola D’Amelio
Pharmaceutics 2022, 14(5), 1089; https://doi.org/10.3390/pharmaceutics14051089 - 19 May 2022
Cited by 3 | Viewed by 2393
Abstract
Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often [...] Read more.
Despite the remarkable similarity in amino acid composition, many anticancer peptides (ACPs) display significant differences in terms of activity. This strongly suggests that particular relative dispositions of amino acids (motifs) play a role in the interaction with their biological target, which is often the cell membrane. To better verify this hypothesis, we intentionally modify HB43, an ACP active against a wide variety of cancers. Sequence alignment of related ACPs by ADAPTABLE web server highlighted the conserved motifs that could be at the origin of the activity. In this study, we show that changing the order of amino acids in such motifs results in a significant loss of activity against colon and breast cancer cell lines. On the contrary, amino acid substitution in key motifs may reinforce or weaken the activity, even when the alteration does not perturb the amphipathicity of the helix formed by HB43 on liposomes mimicking their surface. NMR and MD simulations with different membrane models (micelles, bicelles, and vesicles) indicate that the activity reflects the insertion capability in cancer-mimicking serine-exposing membranes, supported by the insertion of N-terminal phenylalanine in the FAK motif and the anchoring to the carboxylate of phosphatidylserine by means of arginine side chains. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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18 pages, 12808 KiB  
Article
Therapeutic Effects of Synthetic Triblock Amphiphilic Short Antimicrobial Peptides on Human Lung Adenocarcinoma
by Danjing Yang, Liang Zhu, Xiangyu Lin, Jiaming Zhu, Yusheng Qian, Wenhui Liu, Jianjun Chen, Chuncai Zhou and Jing He
Pharmaceutics 2022, 14(5), 929; https://doi.org/10.3390/pharmaceutics14050929 - 24 Apr 2022
Cited by 4 | Viewed by 2214
Abstract
Because of their unique properties, antimicrobial peptides (AMPs) represent a potential reservoir of novel anticancer therapeutic agents. However, only a few AMPs can kill tumors with high efficiency, and obtaining inexpensive anticancer AMPs with strong activity is still a challenge. In our previous [...] Read more.
Because of their unique properties, antimicrobial peptides (AMPs) represent a potential reservoir of novel anticancer therapeutic agents. However, only a few AMPs can kill tumors with high efficiency, and obtaining inexpensive anticancer AMPs with strong activity is still a challenge. In our previous work, a series of original short amphiphilic triblock AMP (KnFmKn) analogues were developed which were demonstrated to exert excellent effects on bacterial infection, both in vitro and in vivo. Herein, the overall objectives were to assess the potent tumoricidal capacities of these analogues against human lung cancer cell line A549 and the underlying mechanism. The results of the CCK-8 assay revealed that the precise modification of the peptides’ primary sequences could modulate their tumoricidal potency. In the tumoricidal progress, positive charge and hydrophobicity were the key driving forces. Among these peptides, K4F6K4 displayed the most remarkable tumoricidal activity. Furthermore, the excellent anticancer capacity of K4F6K4 was proven by the live/dead cell staining, colony formation assay, and tumor growth observations on xenografted mice, which indicated that K4F6K4 might be a promising drug candidate for lung cancer, with no significant adverse effects in vitro or in vivo. In addition, the cell apoptosis assay using flow cytometry, the morphology observations using the optical microscope, confocal microscopy using CellMask™ Deep Red staining, and scanning electron microscope suggested that membrane disruption was the primary mechanism of its antitumor action. Through analyzing the structure–activity relationship, it was found that the amount of positive charge required for KnFmKn to exert its optimal tumoricidal effect was more than that needed for the antimicrobial activity, while the optimal proportion of hydrophobicity was less. Our findings suggest that further analysis of the structure–activity relationship of AMPs’ primary sequence variations will be beneficial. Hopefully, this work can provide guiding principles in designing peptide-based therapeutics for lung cancer. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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28 pages, 4361 KiB  
Article
Circumsporozoite Protein of Plasmodium berghei- and George Baker Virus A-Derived Peptides Trigger Efficient Cell Internalization of Bioconjugates and Functionalized Poly(ethylene glycol)-b-poly(benzyl malate)-Based Nanoparticles in Human Hepatoma Cells
by Elise Vène, Kathleen Jarnouen, Catherine Ribault, Manuel Vlach, Yann Verres, Mickaël Bourgeois, Nicolas Lepareur, Sandrine Cammas-Marion and Pascal Loyer
Pharmaceutics 2022, 14(4), 804; https://doi.org/10.3390/pharmaceutics14040804 - 6 Apr 2022
Cited by 4 | Viewed by 1833
Abstract
In order to identify the peptides, selected from the literature, that exhibit the strongest tropism towards human hepatoma cells, cell uptake assays were performed using biotinylated synthetic peptides bound to fluorescent streptavidin or engrafted onto nanoparticles (NPs), prepared from biotin-poly(ethylene glycol)-block-poly(benzyl [...] Read more.
In order to identify the peptides, selected from the literature, that exhibit the strongest tropism towards human hepatoma cells, cell uptake assays were performed using biotinylated synthetic peptides bound to fluorescent streptavidin or engrafted onto nanoparticles (NPs), prepared from biotin-poly(ethylene glycol)-block-poly(benzyl malate) (Biot-PEG-b-PMLABe) via streptavidin bridging. Two peptides, derived from the circumsporozoite protein of Plasmodium berghei- (CPB) and George Baker (GB) Virus A (GBVA10-9), strongly enhanced the endocytosis of both streptavidin conjugates and NPs in hepatoma cells, compared to primary human hepatocytes and non-hepatic cells. Unexpectedly, the uptake of CPB- and GBVA10-9 functionalized PEG-b-PMLABe-based NPs by hepatoma cells involved, at least in part, the peptide binding to apolipoproteins, which would promote NP’s interactions with cell membrane receptors of HDL particles. In addition, CPB and GBVA10-9 peptide–streptavidin conjugates favored the uptake by hepatoma cells over that of the human macrophages, known to strongly internalize nanoparticles by phagocytosis. These two peptides are promising candidate ligands for targeting hepatocellular carcinomas. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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18 pages, 3295 KiB  
Article
New Intracellular Peptide Derived from Hemoglobin Alpha Chain Induces Glucose Uptake and Reduces Blood Glycemia
by Renée N. O. Silva, Ricardo P. Llanos, Rosangela A. S. Eichler, Thiago B. Oliveira, Fábio C. Gozzo, William T. Festuccia and Emer S. Ferro
Pharmaceutics 2021, 13(12), 2175; https://doi.org/10.3390/pharmaceutics13122175 - 16 Dec 2021
Cited by 3 | Viewed by 2960
Abstract
Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of [...] Read more.
Intracellular peptides were shown to derive from proteasomal degradation of proteins from mammalian and yeast cells, being suggested to play distinctive roles both inside and outside these cells. Here, the role of intracellular peptides previously identified from skeletal muscle and adipose tissues of C57BL6/N wild type (WT) and neurolysin knockout mice were investigated. In differentiated C2C12 mouse skeletal muscle cells, some of these intracellular peptides like insulin activated the expression of several genes related to muscle contraction and gluconeogenesis. One of these peptides, LASVSTVLTSKYR (Ric4; 600 µg/kg), administrated either intraperitoneally or orally in WT mice, decreased glycemia. Neither insulin (10 nM) nor Ric4 (100 µM) induced glucose uptake in adipose tissue explants obtained from conditional knockout mice depleted of insulin receptor. Ric4 (100 µM) similarly to insulin (100 nM) induced Glut4 translocation to the plasma membrane of C2C12 differentiated cells, and increased GLUT4 mRNA levels in epididymal adipose tissue of WT mice. Ric4 (100 µM) increased both Erk and Akt phosphorylation in C2C12, as well as in epididymal adipose tissue from WT mice; Erk, but not Akt phosphorylation was activated by Ric4 in tibial skeletal muscle from WT mice. Ric4 is rapidly degraded in vitro by WT liver and kidney crude extracts, such a response that is largely reduced by structural modifications such as N-terminal acetylation, C-terminal amidation, and substitution of Leu8 for DLeu8 (Ac-LASVSTV[DLeu]TSKYR-NH2; Ric4-16). Ric4-16, among several Ric4 derivatives, efficiently induced glucose uptake in differentiated C2C12 cells. Among six Ric4-derivatives evaluated in vivo, Ac-LASVSTVLTSKYR-NH2 (Ric4-2; 600 µg/kg) and Ac-LASVSTV[DLeu]TSKYR (Ric4-15; 600 µg/kg) administrated orally efficiently reduced glycemia in a glucose tolerance test in WT mice. The potential clinical application of Ric4 and Ric4-derivatives deserves further attention. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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19 pages, 4233 KiB  
Article
Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
by Javad Garousi, Haozhong Ding, Emma von Witting, Tianqi Xu, Anzhelika Vorobyeva, Maryam Oroujeni, Anna Orlova, Sophia Hober, Torbjörn Gräslund and Vladimir Tolmachev
Pharmaceutics 2021, 13(11), 1847; https://doi.org/10.3390/pharmaceutics13111847 - 3 Nov 2021
Cited by 5 | Viewed by 2673
Abstract
Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor [...] Read more.
Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusion with an albumin binding domain (ABD), and armed it with the highly cytotoxic payload mertansine (DM1) for an investigation of its properties in vitro and in vivo. The resulting drug conjugate, ADAPT6-ABD-mcDM1, retained binding to its intended targets, namely HER2 and serum albumins. Further, it was able to specifically bind to cells with high HER2 expression, get internalized, and showed potent toxicity, with IC50 values ranging from 5 to 80 nM. Conversely, no toxic effect was found for cells with low HER2 expression. In vivo, ADAPT6-ABD-mcDM1, radiolabeled with 99mTc, was characterized by low uptake in most normal organs, and the main excretion route was shown to be through the kidneys. The tumor uptake was 5.5% ID/g after 24 h, which was higher than the uptake in all normal organs at this time point except for the kidneys. The uptake in the tumors was blockable by pre-injection of an excess of the monoclonal antibody trastuzumab (having an overlapping epitope on the HER2 receptor). In conclusion, half-life extended drug conjugates based on the ADAPT platform of affinity proteins holds promise for further development towards targeted cancer therapy. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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Review

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20 pages, 1751 KiB  
Review
Role of Anti-Cancer Peptides as Immunomodulatory Agents: Potential and Design Strategy
by Amit Kumar Tripathi and Jamboor K. Vishwanatha
Pharmaceutics 2022, 14(12), 2686; https://doi.org/10.3390/pharmaceutics14122686 - 1 Dec 2022
Cited by 13 | Viewed by 3874
Abstract
The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment. [...] Read more.
The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment. For a long time, antimicrobial peptides (AMPs) have been shown to display anticancer activity. However, the immunomodulatory activity of anti-cancer peptides has not been researched very extensively. The interconnection of cancer and immune responses is well-known. Hence, a search and design of molecules that can show anti-cancer and immunomodulatory activity can be lead molecules in this field. A large number of anti-cancer peptides show good immunomodulatory activity by inhibiting the pro-inflammatory responses that assist cancer progression. Here, we thoroughly review both the naturally occurring and synthetic anti-cancer peptides that are reported to possess both anti-cancer and immunomodulatory activity. We also assess the structural and biophysical parameters that can be utilized to improve the activity. Both activities are mostly reported by different groups, however, we discuss them together to highlight their interconnection, which can be used in the future to design peptide drugs in the field of cancer therapeutics. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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21 pages, 2301 KiB  
Review
Development of Anticancer Peptides Using Artificial Intelligence and Combinational Therapy for Cancer Therapeutics
by Ji Su Hwang, Seok Gi Kim, Tae Hwan Shin, Yong Eun Jang, Do Hyeon Kwon and Gwang Lee
Pharmaceutics 2022, 14(5), 997; https://doi.org/10.3390/pharmaceutics14050997 - 6 May 2022
Cited by 18 | Viewed by 4862
Abstract
Cancer is a group of diseases causing abnormal cell growth, altering the genome, and invading or spreading to other parts of the body. Among therapeutic peptide drugs, anticancer peptides (ACPs) have been considered to target and kill cancer cells because cancer cells have [...] Read more.
Cancer is a group of diseases causing abnormal cell growth, altering the genome, and invading or spreading to other parts of the body. Among therapeutic peptide drugs, anticancer peptides (ACPs) have been considered to target and kill cancer cells because cancer cells have unique characteristics such as a high negative charge and abundance of microvilli in the cell membrane when compared to a normal cell. ACPs have several advantages, such as high specificity, cost-effectiveness, low immunogenicity, minimal toxicity, and high tolerance under normal physiological conditions. However, the development and identification of ACPs are time-consuming and expensive in traditional wet-lab-based approaches. Thus, the application of artificial intelligence on the approaches can save time and reduce the cost to identify candidate ACPs. Recently, machine learning (ML), deep learning (DL), and hybrid learning (ML combined DL) have emerged into the development of ACPs without experimental analysis, owing to advances in computer power and big data from the power system. Additionally, we suggest that combination therapy with classical approaches and ACPs might be one of the impactful approaches to increase the efficiency of cancer therapy. Full article
(This article belongs to the Special Issue Peptide-Based Drugs for Cancer Therapies)
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