Peptoids and Peptide Based Drugs

Topic Information

Dear Colleagues,

Over the last few decades, peptides have gained increasing interest as attractive drugs due to their unique ability to combine the advantages of antibodies and small molecules and the more favorable specificity and selectivity for their targets. Today, over 80 peptide-based therapeutic agents have been approved by the FDA, and many more are in clinical development. Therapeutic peptides have been identified from various sources, such as living organisms, synthetic chemical libraries, genetic or recombinant libraries, and bioinformatic approaches. They commonly act as hormones, growth factors, neurotransmitters, ion channel ligands, or anti-infective agents, bind to cell surface receptors, and trigger intracellular effects with high affinity and specificity. Recently, the ability of peptides to effectively and selectively inhibit PPIs has also been demonstrated, opening the doors for peptide therapeutics to reach the currently "undruggable" space. Despite these advantages, some peptides still suffer from drawbacks such as poor cellular permeability and high metabolic instability. An attractive alternative that overcomes these challenges is developing peptidomimetics-based therapeutics that are physiologically stable and have high cellular permeability. One class of peptidomimetics, which is an excellent candidate for this purpose, is peptoids, N-substituted glycine oligomers. Peptoids can be synthesized on solid support from primary amines, allowing to introduce a variety of functional groups within their sequence. They can fold into well-defined secondary structures in solution and could be employed in various biological activities, including protein–protein interactions and selective extraction of metal ions. Importantly, peptoids, which cannot form hydrogen bonding because they comprise a tertiary amide backbone, display a significantly improved stability profile in vivo, are more lipophilic than peptides, and have some intriguing pharmacological properties: they are stable against proteases and peptidases, are tolerant towards high salt concentration and various pH conditions, and have better bioavailability and better cell permeability than peptides. Due to these advantages, peptoids are becoming attractive candidates for therapeutic and diagnostic applications. To date, peptoids have demonstrated bioactivity as protein mimics and as replacements for small molecule drugs. Recent advances in research on peptoid as therapeutics in the last several years include in vitro and in vivo studies in the fields of lung surfactant therapy, antimicrobial agents, diagnostics, and anticancer agents and inhibitors. Some of these peptoids are designed de novo, while others are prepared by converting interesting peptides into peptoids. The latter, however, is associated with a reduction in the biological activity related to even minor structural changes, and the development of peptide–peptoid chimeras (peptomers) can help in creating better peptoid-based therapeutics.

Dr. Laura Zaccaro
Dr. Annarita Del Gatto
Dr. Galia Maayan
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	3.9	5.2	2013	15.3 Days	CHF 2600	Submit
Journal of Clinical Medicine jcm	3.0	5.7	2012	17.3 Days	CHF 2600	Submit
Pharmaceuticals pharmaceuticals	4.3	6.1	2004	12.8 Days	CHF 2900	Submit
Pharmaceutics pharmaceutics	4.9	7.9	2009	14.9 Days	CHF 2900	Submit
Pharmacy pharmacy	2.0	-	2013	22.9 Days	CHF 1800	Submit
International Journal of Molecular Sciences ijms	4.9	8.1	2000	18.1 Days	CHF 2900	Submit
Molecules molecules	4.2	7.4	1996	15.1 Days	CHF 2700	Submit
Biophysica biophysica	-	1.6	2021	17.7 Days	CHF 1000	Submit

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Published Papers (8 papers)

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All Biomedicines JCM Pharmaceuticals Pharmaceutics Pharmacy IJMS Molecules Biophysica

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13 pages, 3205 KiB  

Open AccessArticle

From In Vitro Promise to In Vivo Reality: An Instructive Account of Infection Model Evaluation of Antimicrobial Peptides

by Adam Carrera-Aubesart, Jiarui Li, Estefanía Contreras, Roberto Bello-Madruga, Marc Torrent and David Andreu

Int. J. Mol. Sci. 2024, 25(18), 9773; https://doi.org/10.3390/ijms25189773 - 10 Sep 2024

Viewed by 792

Abstract

Antimicrobial peptides (AMPs) are regarded as a promising alternative to traditional antibiotics in the face of ever-increasing resistance. However, many AMPs fail to progress into clinics due to unexpected difficulties found in preclinical in vivo phases. Our research has focused on crotalicidin (Ctn), [...] Read more.

Antimicrobial peptides (AMPs) are regarded as a promising alternative to traditional antibiotics in the face of ever-increasing resistance. However, many AMPs fail to progress into clinics due to unexpected difficulties found in preclinical in vivo phases. Our research has focused on crotalicidin (Ctn), an AMP from snake venom, and a fragment thereof, Ctn[15-34], with improved in vitro antimicrobial and anticancer activities and remarkable serum stability. As the retroenantio versions of both AMPs maintained favorable profiles, in this work, we evaluate the in vivo efficacy of both the native-sequence AMPs and their retroenantio counterparts in a murine infection model with Acinetobacter baumannii. A significant reduction in bacterial levels is found in the mice treated with Ctn[15-34]. However, contrary to expectations, the retroenantio analogs either exhibit toxicity or lack efficacy when administered to mice. Our findings underscore the critical importance of in vivo infection model evaluation to fully calibrate the therapeutic potential of AMPs. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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17 pages, 3486 KiB  

Open AccessArticle

Opioid/Dopamine Receptor Binding Studies, NMR and Molecular Dynamics Simulation of LENART01 Chimera, an Opioid-Bombesin-like Peptide

by Pawel Serafin, Łukasz Szeleszczuk, Igor Zhukov, Edina Szűcs, Dávid Gombos, Azzurra Stefanucci, Adriano Mollica, Dariusz Maciej Pisklak and Patrycja Kleczkowska

Molecules 2024, 29(1), 272; https://doi.org/10.3390/molecules29010272 - 4 Jan 2024

Cited by 3 | Viewed by 1681

Abstract

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the [...] Read more.

The design and development of hybrid compounds as a new class of drug candidates remains an excellent opportunity to improve the pharmacological properties of drugs (including enzymatic stability, efficacy and pharmacokinetic and pharmacodynamic profiles). In addition, considering various complex diseases and/or disorders, the conjugate chemistry approach is highly acceptable and justified. Opioids have long been recognized as the most potent analgesics and serve as the basic pharmacophore for potent hybrid compounds that may be useful in pain management. However, a risk of tolerance and physical dependence exists. Since dopamine receptors have been implicated in the aforementioned adverse effects of opioids, the construction of a hybrid with dual action at opioid and dopamine receptors is of interest. Herein, we present nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics simulation results for LENART01, an opioid–ranatensin hybrid peptide. Apart from molecular docking, protein–ligand interactions were also assessed in vitro using a receptor binding assay, which proved LENART01 to be bound to mu-opioid and dopamine receptors, respectively. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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15 pages, 1908 KiB  

Open AccessReview

Peptoids: Smart and Emerging Candidates for the Diagnosis of Cancer, Neurological and Autoimmune Disorders

by Anna Giorgio, Annarita Del Gatto, Simone Pennacchio, Michele Saviano and Laura Zaccaro

Int. J. Mol. Sci. 2023, 24(22), 16333; https://doi.org/10.3390/ijms242216333 - 15 Nov 2023

Cited by 1 | Viewed by 1413

Abstract

Early detection of fatal and disabling diseases such as cancer, neurological and autoimmune dysfunctions is still desirable yet challenging to improve quality of life and longevity. Peptoids (N-substituted glycine oligomers) are a relatively new class of peptidomimetics, being highly versatile and capable of [...] Read more.

Early detection of fatal and disabling diseases such as cancer, neurological and autoimmune dysfunctions is still desirable yet challenging to improve quality of life and longevity. Peptoids (N-substituted glycine oligomers) are a relatively new class of peptidomimetics, being highly versatile and capable of mimicking the architectures and the activities of the peptides but with a marked resistance to proteases and a propensity to cross the cellular membranes over the peptides themselves. For these properties, they have gained an ever greater interest in applications in bioengineering and biomedical fields. In particular, the present manuscript is to our knowledge the only review focused on peptoids for diagnostic applications and covers the last decade’s literature regarding peptoids as tools for early diagnosis of pathologies with a great impact on human health and social behavior. The review indeed provides insights into the peptoid employment in targeted cancer imaging and blood-based screening of neurological and autoimmune diseases, and it aims to attract the scientific community’s attention to continuing and sustaining the investigation of these peptidomimetics in the diagnosis field considering their promising peculiarities. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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18 pages, 2712 KiB  

Open AccessReview

Bombesins: A New Frontier in Hybrid Compound Development

by Pawel Serafin and Patrycja Kleczkowska

Pharmaceutics 2023, 15(11), 2597; https://doi.org/10.3390/pharmaceutics15112597 - 7 Nov 2023

Cited by 4 | Viewed by 1616

Abstract

Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. [...] Read more.

Recently, bombesin (BN) and its analogs have attracted much attention as excellent anticancer agents because they interact with specific receptors widely distributed on the surface of various cancer cells. However, their biological properties proceed far beyond this, given a broad spectrum of activity. Bombesin receptor ligands are effective drugs for the treatment of rheumatoid arthritis or gastrointestinal diseases. However, most diseases are complex, and the use of polytherapy may lead to pharmacokinetic and pharmacodynamic drug–drug interactions, resulting in side effects. Therefore, there is a need to develop effective compounds that also contain BN or its analogs, which are combined with other structural entities, thus generating a so-called hybrid drug. Hybrid drugs that contain bombesin pharmacophore(s) may be proposed as a solution to the problem of polytherapy or the lack of an effective cure. Such structures have now demonstrated the desired efficacy, though information on these aforementioned compounds is relatively scarce. Therefore, our paper aims to encourage researchers to focus on bombesins. Herein, we indicate that the hybrid approach should also be firmly applied to bombesins and the BN receptor family. This paper’s structure is divided into two main sections demonstrating bombesins and their properties, as well as recent data on bombesin-based hybrid compounds and their potential usefulness in medicine. Overall, it refers to the discovery and synthesis of modified bombesin-based hybrid compounds. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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17 pages, 3574 KiB  

Open AccessArticle

The Synthetic Peptide GA-Hecate and Its Analogs Inhibit Multiple Steps of the Chikungunya Virus Infection Cycle In Vitro

by Gabriela Miranda Ayusso, Paulo Ricardo da Silva Sanches, Tamara Carvalho, Igor Andrade Santos, Daniel Oliveira Silva Martins, Maria Letícia Duarte Lima, Pâmela Jóyce Previdelli da Conceição, Cíntia Bittar, Andres Merits, Eduardo Maffud Cilli, Ana Carolina Gomes Jardim, Paula Rahal and Marilia Freitas Calmon

Pharmaceuticals 2023, 16(10), 1389; https://doi.org/10.3390/ph16101389 - 30 Sep 2023

Cited by 2 | Viewed by 1555

Abstract

Chikungunya virus (CHIKV) belongs to the Alphavirus genus and is responsible for significant outbreaks worldwide. Currently, there is no approved antiviral therapy against CHIKV. Bioactive peptides have great potential for new drug development. Here, we evaluated the antiviral activity of the synthetic peptide [...] Read more.

Chikungunya virus (CHIKV) belongs to the Alphavirus genus and is responsible for significant outbreaks worldwide. Currently, there is no approved antiviral therapy against CHIKV. Bioactive peptides have great potential for new drug development. Here, we evaluated the antiviral activity of the synthetic peptide GA-Hecate and its analogs PSSct1905 and PSSct1910 against CHIKV infection. Initial screening showed that all three peptides inhibited the CHIKV replication cycle in baby hamster kidney fibroblast cells (BHK-21) and human hepatocarcinoma epithelial cells (Huh-7). GA-Hecate and its analog PSSct1905 were the most active, demonstrating suppression of viral infection by more than 91%. The analog PSSct1905 exhibited a protective effect in cells against CHIKV infection. We also observed that the analogs PSSct1905 and PSSct1910 affected CHIKV entry into both cell lines, inhibiting viral attachment and internalization. Finally, all tested compounds presented antiviral activity on the post-entry steps of CHIKV infection in all cells evaluated. In conclusion, this study highlights the potential of the peptide GA-Hecate and its analogs as novel anti-CHIKV compounds targeting different stages of the viral replication cycle, warranting the development of GA-Hecate-based compounds with broad antiviral activity. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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32 pages, 2470 KiB  

Open AccessReview

Peptide Vaccines as Therapeutic and Prophylactic Agents for Female-Specific Cancers: The Current Landscape

by Manju Lekshmy, Chandrasekharan Rajalekshmi Dhanya, Jayashree SatheeshKumar Smrithi, Janaki Anandavallyamma Sindhurani, Jiji Joseph Vandanamthadathil, Jayakrishnan Therthala Veettil, Leelamma Anila, Vishnu Sasidharan Lathakumari, Adhira M. Nayar and Maya Madhavan

Pharmaceuticals 2023, 16(7), 1054; https://doi.org/10.3390/ph16071054 - 24 Jul 2023

Cited by 2 | Viewed by 4597

Abstract

Breast and gynecologic cancers are significant global threats to women’s health and those living with the disease require lifelong physical, financial, and social support from their families, healthcare providers, and society as a whole. Cancer vaccines offer a promising means of inducing long-lasting [...] Read more.

Breast and gynecologic cancers are significant global threats to women’s health and those living with the disease require lifelong physical, financial, and social support from their families, healthcare providers, and society as a whole. Cancer vaccines offer a promising means of inducing long-lasting immune response against the disease. Among various types of cancer vaccines available, peptide vaccines offer an effective strategy to elicit specific anti-tumor immune responses. Peptide vaccines have been developed based on tumor associated antigens (TAAs) and tumor specific neoantigens which can also be of viral origin. Molecular alterations in HER2 and non-HER2 genes are established to be involved in the pathogenesis of female-specific cancers and hence were exploited for the development of peptide vaccines against these diseases, most of which are in the latter stages of clinical trials. However, prophylactic vaccines for viral induced cancers, especially those against Human Papillomavirus (HPV) infection are well established. This review discusses therapeutic and prophylactic approaches for various types of female-specific cancers such as breast cancer and gynecologic cancers with special emphasis on peptide vaccines. We also present a pipeline for the design and evaluation of a multiepitope peptide vaccine that can be active against female-specific cancers. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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25 pages, 6578 KiB  

Open AccessReview

Review: Structure-Activity Relationship of Antimicrobial Peptoids

by Priscilla L. Nyembe, Thandokuhle Ntombela and Maya M. Makatini

Pharmaceutics 2023, 15(5), 1506; https://doi.org/10.3390/pharmaceutics15051506 - 15 May 2023

Cited by 10 | Viewed by 2537

Abstract

Due to their broad-spectrum activity against Gram-negative and Gram-positive bacteria, natural antimicrobial peptides (AMPs) and their synthetic analogs have emerged as prospective therapies for treating illnesses brought on by multi-drug resistant pathogens. To overcome the limitations of AMPs, such as protease degradation, oligo-N-substituted [...] Read more.

Due to their broad-spectrum activity against Gram-negative and Gram-positive bacteria, natural antimicrobial peptides (AMPs) and their synthetic analogs have emerged as prospective therapies for treating illnesses brought on by multi-drug resistant pathogens. To overcome the limitations of AMPs, such as protease degradation, oligo-N-substituted glycines (peptoids) are a promising alternative. Despite having the same backbone atom sequence as natural peptides, peptoid structures are more stable because, unlike AMP, their functional side chains are attached to the backbone nitrogen (N)-atom rather than the alpha carbon atom. As a result, peptoid structures are less susceptible to proteolysis and enzymatic degradation. The advantages of AMPs, such as hydrophobicity, cationic character, and amphipathicity, are mimicked by peptoids. Furthermore, structure-activity relationship studies (SAR) have shown that tuning the structure of peptoids is a crucial step in developing effective antimicrobials. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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24 pages, 1597 KiB  

Open AccessReview

Designing Formulation Strategies for Enhanced Stability of Therapeutic Peptides in Aqueous Solutions: A Review

by Primawan Putra Nugrahadi, Wouter L. J. Hinrichs, Henderik W. Frijlink, Christian Schöneich and Christina Avanti

Pharmaceutics 2023, 15(3), 935; https://doi.org/10.3390/pharmaceutics15030935 - 14 Mar 2023

Cited by 19 | Viewed by 6804

Abstract

Over the past few decades, there has been a tremendous increase in the utilization of therapeutic peptides. Therapeutic peptides are usually administered via the parenteral route, requiring an aqueous formulation. Unfortunately, peptides are often unstable in aqueous solutions, affecting stability and bioactivity. Although [...] Read more.

Over the past few decades, there has been a tremendous increase in the utilization of therapeutic peptides. Therapeutic peptides are usually administered via the parenteral route, requiring an aqueous formulation. Unfortunately, peptides are often unstable in aqueous solutions, affecting stability and bioactivity. Although a stable and dry formulation for reconstitution might be designed, from a pharmaco-economic and practical convenience point of view, a peptide formulation in an aqueous liquid form is preferred. Designing formulation strategies that optimize peptide stability may improve bioavailability and increase therapeutic efficacy. This literature review provides an overview of various degradation pathways and formulation strategies to stabilize therapeutic peptides in aqueous solutions. First, we introduce the major peptide stability issues in liquid formulations and the degradation mechanisms. Then, we present a variety of known strategies to inhibit or slow down peptide degradation. Overall, the most practical approaches to peptide stabilization are pH optimization and selecting the appropriate type of buffer. Other practical strategies to reduce peptide degradation rates in solution are the application of co-solvency, air exclusion, viscosity enhancement, PEGylation, and using polyol excipients. Full article

(This article belongs to the Topic Peptoids and Peptide Based Drugs)

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