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Pharmaceuticals
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Small Molecules and Peptides in Drug Discovery
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Small Molecules and Peptides in Drug Discovery

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 21763

Special Issue Editors

Dr. Susanna Nencetti

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Guest Editor
Associate Professor, Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: medicinal chemistry; drug discovery; metalloenzyme inhibitors; neurodegenerative diseases; anticancer drugs; CNS agents; chemical synthesis; structure–activity relationship; natural products
Special Issues, Collections and Topics in MDPI journals
Dr. Nicolo Tonali

E-Mail Website
Guest Editor
BioCIS, Université Paris-Saclay, Faculté de Pharmacie, 91400 Paris, France
Interests: amyloid; foldamers; protein-protein interactions; peptides; peptidomimetics
Special Issues, Collections and Topics in MDPI journals
Dr. Lidia Ciccone

E-Mail Website
Guest Editor
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: amyloid proteins; medicinal chemistry; degenerative diseases; drug design; X-ray crystallography; chemical synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, an increasing number of studies have been published focusing on the therapeutic use of small molecule drugs in oncology, infectiology, and general pathology, especially inflammatory processes. Interesting data on possible therapeutic applications of small molecules, both natural and synthetic, for the treatment of neuropsychiatric and neurodegenerative illnesses are emerging. For small molecules that act in the nervous system, brain bioavailability is an important challenge. Most drugs reach the brain predominantly through a non-saturable mechanism of transcellular diffusion that increases the interest in their development as therapeutics tools. On the other hand, some neuroprotective drugs show limited therapeutic efficacy due to ineffective transport across the blood–brain barrier. Recent approaches such as the use of nanomaterials as drug transport systems open new possibilities in the development of neurological agents targeting the central nervous system.

Peptide-based therapeutics have a relevant role in the treatment of neurodegenerative diseases and cancer, especially when the main challenge is represented by the modulation of large and relatively flexible surface areas, typically found in protein–protein interactions. Research in this field has been oriented toward peptides because they offer several advantages such as greater efficacy, specificity, and selectivity, owing to their intermediate size between small molecule drugs and protein therapeutics. Moreover, the risk of complication caused by their metabolites is reduced, thus making them safer. Over the past decade, foldamers have increasingly attracted attention as useful tools to mimic secondary structures of peptides. In this regard, peptidomimetic foldamers represent a pharmacologically important class of compounds, as they are inspired by the structural features of their bioactive peptide counterparts.

In this Special Issue entitled “Small Molecules and Peptides in Drug Discovery”, we wish to focus on the design, synthesis, and application of synthetic as well as natural-based small molecules and peptides for successful therapies against neurodegenerative diseases and cancer, particularly those involving protein–protein interactions and membrane passage issues. Research articles, comprehensive reviews, and short communications will be welcome, with the aim of collecting the most recent insights and results in therapeutic applications involving multidisciplinary approaches and addressing various pharmacological issues.

Prof. Dr. Susanna Nencetti
Dr. Nicolo Tonali
Dr. Lidia Ciccone
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • drug discovery
  • small molecules
  • natural compounds
  • peptides
  • peptidomimetic
  • foldamer
  • metalloenzyme inhibitors
  • neurodegenerative diseases
  • multifunctional ligands
  • nanoformulations

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Published Papers (6 papers)

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Research

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18 pages, 7900 KiB  
Article
Identification of a Novel p53 Modulator Endowed with Antitumoural and Antibacterial Activity through a Scaffold Repurposing Approach
by Elisa Nuti, Valeria La Pietra, Simona Daniele, Doretta Cuffaro, Lidia Ciccone, Chiara Giacomelli, Carolina Cason, Alfonso Carotenuto, Vincenzo Maria D’Amore, Eleonora Da Pozzo, Barbara Costa, Riccardo Di Leo, Manola Comar, Luciana Marinelli, Claudia Martini and Armando Rossello
Pharmaceuticals 2022, 15(11), 1318; https://doi.org/10.3390/ph15111318 - 26 Oct 2022
Cited by 1 | Viewed by 1698
Abstract
Intracellular pathogens, such as Chlamydia trachomatis, have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53–MDM2 complex could reduce infection and restore pro-apoptotic effect [...] Read more.
Intracellular pathogens, such as Chlamydia trachomatis, have been recently shown to induce degradation of p53 during infection, thus impairing the protective response of the host cells. Therefore, p53 reactivation by disruption of the p53–MDM2 complex could reduce infection and restore pro-apoptotic effect of p53. Here, we report the identification of a novel MDM2 inhibitor with potential antitumoural and antibacterial activity able to reactivate p53. A virtual screening was performed on an in-house chemical library, previously synthesised for other targets, and led to the identification of a hit compound with a benzo[a]dihydrocarbazole structure, RM37. This compound induced p53 up-regulation in U343MG glioblastoma cells by blocking MDM2–p53 interaction and reduced tumour cell growth. NMR studies confirmed its ability to dissociate the MDM2–p53 complex. Notably, RM37 reduced Chlamydia infection in HeLa cells in a concentration-dependent manner and ameliorated the inflammatory status associated with infection. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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17 pages, 1096 KiB  
Article
Synthesis and Biological Activity Characterization of Novel 5-Oxopyrrolidine Derivatives with Promising Anticancer and Antimicrobial Activity
by Karolina Kairytė, Birutė Grybaitė, Rita Vaickelionienė, Birutė Sapijanskaitė-Banevič, Povilas Kavaliauskas and Vytautas Mickevičius
Pharmaceuticals 2022, 15(8), 970; https://doi.org/10.3390/ph15080970 - 6 Aug 2022
Cited by 7 | Viewed by 2367
Abstract
The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. [...] Read more.
The 1-(4-acetamidophenyl)-5-oxopyrrolidine carboxylic acid was applied for synthesizing derivatives bearing azole, diazole, and hydrazone moieties in the molecule. Modification of an acetamide fragment to the free amino group afforded compounds with two functional groups, which enabled to provide a series of 4-substituted-1-(4-substituted phenyl)pyrrolidine-2-ones. The resulted compounds 2 and 4–22 were subjected to the in vitro anticancer and antimicrobial activity determination. The compounds 18–22 exerted the most potent anticancer activity against A549 cells. Furthermore, compound 21 bearing 5-nitrothiophene substituents demonstrated promising and selective antimicrobial activity against multidrug-resistant Staphylococcus aureus strains, including linezolid and tedizolid-resistant S. aureus. These results demonstrate that 5-oxopyrolidine derivatives are attractive scaffolds for the further development of anticancer and antimicrobial compounds targeting multidrug-resistant Gram-positive pathogens. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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20 pages, 7351 KiB  
Communication
Novel Potent and Selective Agonists of the GPR55 Receptor Based on the 3-Benzylquinolin-2(1H)-One Scaffold
by Costanza Ceni, Michael J. Benko, Kawthar A. Mohamed, Giulio Poli, Miriana Di Stefano, Tiziano Tuccinardi, Maria Digiacomo, Massimo Valoti, Robert B. Laprairie, Marco Macchia and Simone Bertini
Pharmaceuticals 2022, 15(7), 768; https://doi.org/10.3390/ph15070768 - 21 Jun 2022
Cited by 3 | Viewed by 2782
Abstract
A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55′s involvement [...] Read more.
A growing body of evidence underlines the crucial role of GPR55 in physiological and pathological conditions. In fact, GPR55 has recently emerged as a therapeutic target for several diseases, including cancer and neurodegenerative and metabolic disorders. Several lines of evidence highlight GPR55′s involvement in the regulation of microglia-mediated neuroinflammation, although the exact molecular mechanism has not been yet elucidated. Nevertheless, there are only a limited number of selective GPR55 ligands reported in the literature. In this work, we designed and synthesized a series of novel GPR55 ligands based on the 3-benzylquinolin-2(1H)-one scaffold, some of which showed excellent binding properties (with Ki values in the low nanomolar range) and almost complete selectivity over cannabinoid receptors. The full agonist profile of all the new derivatives was assessed using the p-ERK activation assay and a computational study was conducted to predict the key interactions with the binding site of the receptor. Our data outline a preliminary structure–activity relationship (SAR) for this class of molecules at GPR55. Some of our compounds are among the most potent GPR55 agonists developed to date and could be useful as tools to validate this receptor as a therapeutic target. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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20 pages, 3263 KiB  
Article
New Synthetic Analogues of Natural Polyphenols as Sirtuin 1-Activating Compounds
by Giulia Bononi, Lorenzo Flori, Valentina Citi, Cecilia Acciai, Viviana Nocilla, Alma Martelli, Giulio Poli, Tiziano Tuccinardi, Carlotta Granchi, Lara Testai, Vincenzo Calderone and Filippo Minutolo
Pharmaceuticals 2022, 15(3), 339; https://doi.org/10.3390/ph15030339 - 10 Mar 2022
Cited by 3 | Viewed by 3041
Abstract
NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so [...] Read more.
NAD+-dependent deacetylase SIRT1 regulates many different biological processes, thus being involved in pathogenic conditions such as metabolic diseases, neurogenerative disorders and cancer. Notably, experimental evidence underlined that the activation of SIRT1 had promising cardioprotective effects. Consequently, many efforts have been so far devoted to finding new SIRT1 activators, both derived from natural sources or prepared by synthetic procedures. Herein, we discovered new SIRT1-activating derivatives, characterized by phenolic rings spaced by sulfur, nitrogen or oxygen-based central linkers. The newly synthesized derivatives were analyzed in enzymatic assays to determine their ability to activate SIRT1, as compared with that of resveratrol. Among the tested molecules, bisarylaniline compound 10 proved to be the most efficient SIRT1 activator. An evaluation of the effects caused by focused structural variations revealed that its para-hydroxy-substituted diphenyl moiety of 10 was the fundamental structural requirement for achieving good SIRT1 activation. Compound 10 was further investigated in ex vivo studies in isolated and perfused rat hearts submitted to ischemia/reperfusion (I/R), where it showed significant protection of the myocardium against I/R injury. Molecular modeling studies suggest the binding mode of 10 within SIRT1 in the presence of the p53-AMC peptide. Our findings reveal that this chemical scaffold may be used as the starting point to develop a new class of more potent SIRT1 activators as cardioprotective agents. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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19 pages, 2995 KiB  
Article
New Sulfanilamide Derivatives Incorporating Heterocyclic Carboxamide Moieties as Carbonic Anhydrase Inhibitors
by Andrea Angeli, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Roman M. Vydzhak, Svitlana Y. Panchishin, Volodymyr Brovarets, Viviana De Luca, Clemente Capasso, Athina Geronikaki and Claudiu T. Supuran
Pharmaceuticals 2021, 14(8), 828; https://doi.org/10.3390/ph14080828 - 23 Aug 2021
Cited by 13 | Viewed by 3286
Abstract
Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic [...] Read more.
Carbonic Anhydrases (CAs) are ubiquitous metalloenzymes involved in several disease conditions. There are 15 human CA (hCA) isoforms and their high homology represents a challenge for the discovery of potential drugs devoid of off-target side effects. For this reason, many synthetic and pharmacologic research efforts are underway to achieve the full pharmacological potential of CA modulators of activity. We report here a novel series of sulfanilamide derivatives containing heterocyclic carboxamide moieties which were evaluated as CA inhibitors against the physiological relevant isoforms hCA I, II, IX, and XII. Some of them showed selectivity toward isoform hCA II and hCA XII. Molecular docking was performed for some of these compounds on isoforms hCA II and XII to understand the possible interaction with the active site amino acid residues, which rationalized the reported inhibitory activity. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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Review

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27 pages, 1514 KiB  
Review
Traditional and Computational Screening of Non-Toxic Peptides and Approaches to Improving Selectivity
by Alberto A. Robles-Loaiza, Edgar A. Pinos-Tamayo, Bruno Mendes, Josselyn A. Ortega-Pila, Carolina Proaño-Bolaños, Fabien Plisson, Cátia Teixeira, Paula Gomes and José R. Almeida
Pharmaceuticals 2022, 15(3), 323; https://doi.org/10.3390/ph15030323 - 8 Mar 2022
Cited by 34 | Viewed by 6244
Abstract
Peptides have positively impacted the pharmaceutical industry as drugs, biomarkers, or diagnostic tools of high therapeutic value. However, only a handful have progressed to the market. Toxicity is one of the main obstacles to translating peptides into clinics. Hemolysis or hemotoxicity, the principal [...] Read more.
Peptides have positively impacted the pharmaceutical industry as drugs, biomarkers, or diagnostic tools of high therapeutic value. However, only a handful have progressed to the market. Toxicity is one of the main obstacles to translating peptides into clinics. Hemolysis or hemotoxicity, the principal source of toxicity, is a natural or disease-induced event leading to the death of vital red blood cells. Initial screenings for toxicity have been widely evaluated using erythrocytes as the gold standard. More recently, many online databases filled with peptide sequences and their biological meta-data have paved the way toward hemolysis prediction using user-friendly, fast-access machine learning-driven programs. This review details the growing contributions of in silico approaches developed in the last decade for the large-scale prediction of erythrocyte lysis induced by peptides. After an overview of the pharmaceutical landscape of peptide therapeutics, we highlighted the relevance of early hemolysis studies in drug development. We emphasized the computational models and algorithms used to this end in light of historical and recent findings in this promising field. We benchmarked seven predictors using peptides from different data sets, having 7–35 amino acids in length. According to our predictions, the models have scored an accuracy over 50.42% and a minimal Matthew’s correlation coefficient over 0.11. The maximum values for these statistical parameters achieved 100.0% and 1.00, respectively. Finally, strategies for optimizing peptide selectivity were described, as well as prospects for future investigations. The development of in silico predictive approaches to peptide toxicity has just started, but their important contributions clearly demonstrate their potential for peptide science and computer-aided drug design. Methodology refinement and increasing use will motivate the timely and accurate in silico identification of selective, non-toxic peptide therapeutics. Full article
(This article belongs to the Special Issue Small Molecules and Peptides in Drug Discovery)
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