Inflammation is a physiological mechanism used by organisms to defend themselves against infection, restoring homeostasis in damaged tissues. It represents the starting point of several chronic ...diseases such as asthma, skin disorders, cancer, cardiovascular syndrome, arthritis, and neurological diseases. An increasing number of studies highlight the over-expression of inflammatory molecules such as oxidants, cytokines, chemokines, matrix metalloproteinases, and transcription factors into damaged tissues. The treatment of inflammatory disorders is usually linked to the use of unspecific small molecule drugs that can cause undesired side effects. Recently, many efforts are directed to develop alternative and more selective anti-inflammatory therapies, several of them imply the use of peptides. Indeed, peptides demonstrated as elected lead compounds toward several targets for their high specificity as well as recent and innovative synthetic strategies. Several endogenous peptides identified during inflammatory responses showed anti-inflammatory activities by inhibiting, reducing, and/or modulating the expression and activity of mediators. This review aims to discuss the potentialities and therapeutic use of peptides as anti-inflammatory agents in the treatment of different inflammation-related diseases and to explore the importance of peptide-based therapies.
Self-assembling peptides could be considered a novel class of agents able to harvest an array of micro/nanostructures that are highly attractive in the biomedical field. By modifying their amino acid ...composition, it is possible to mime several biological functions; when assembled in micro/nanostructures, they can be used for a variety of purposes such as tissue regeneration and engineering or drug delivery to improve drug release and/or stability and to reduce side effects. Other significant advantages of self-assembled peptides involve their biocompatibility and their ability to efficiently target molecular recognition sites. Due to their intrinsic characteristics, self-assembled peptide micro/nanostructures are capable to load both hydrophobic and hydrophilic drugs, and they are suitable to achieve a triggered drug delivery at disease sites by inserting in their structure's stimuli-responsive moieties. The focus of this review was to summarize the most recent and significant studies on self-assembled peptides with an emphasis on their application in the biomedical field.
The development of synthetic macrocycles represents a powerful approach toward the identification of new protein binders or inhibitors of Protein-Protein Interactions (PPI) which are known to play ...key biological roles in cancer signaling as well as in the regulation of cell division cycle. Structural investigations led to identify "hot loops" sharing common motifs that are mainly involved in PPIs. Most PPIs occur through large and flat surfaces; currently these protein complexes are defined as "undruggable" by conventional drug-discovery approaches, since the identification of small molecules to inhibit these targets is often unreachable. Typically macrocycles are 500-2000 Da in size, having 12-membered, or more, ring architecture: they do not obey the Lipinski's rule but, for them nature offers many examples as therapeutic agents such as erythromycin (antibiotic), cyclosporin (immunosuppressant) and somatostatin (hormone). Peptide-based macrocycles offer the advantages of directly mimicking secondary structures involved in PPIs and their pharmacological application is related to the potential improvement of lead peptides in terms of potency, selectivity, stability and cell permeation. The promising relevance of cyclopeptides prompted to develop new synthetic methods for cyclization: often biotechnological approaches as well as regioselective reactions have been employed to cyclize peptides rapidly and nearly quantitatively. Moreover, different synthetic strategies in peptidomimetics' macrocyclization are actually available based on surrogate peptide bonds or NCL (Native Chemical Ligation) methods. In this review we focus on the most common methods for the preparation of cyclopeptides and interesting applications of the last decade.
Acute myeloid leukemia (AML) is a heterogeneous group of diseases classified into various types on the basis of distinct features concerning the morphology, cytochemistry and cytogenesis of leukemic ...cells. Among the different subtypes, the group "AML with gene mutations" includes the variations of the gene of the multifunctional protein nucleophosmin 1 (NPM1). These mutations are the most frequent (~30-35% of AML adult patients and less in pediatric ones) and occur predominantly in the C-terminal domain (CTD) of NPM1. The most important mutation is the insertion at W288, which determines the frame shift W288Cfs12/Ffs12/Lfs*12 and leads to the addition of 2-12 amino acids, which hamper the correct folding of NPM1. This mutation leads to the loss of the nuclear localization signal (NoLS) and to aberrant cytoplasmic localization, denoted as NPM1c+. Many investigations demonstrated that interfering with the cellular location and oligomerization status of NPM1 can influence its biological functions, including the proper buildup of the nucleolus, and therapeutic strategies have been proposed to target NPM1c+, particularly the use of drugs able to re-direct NPM1 localization. Our studies unveiled a direct link between AML mutations and the neat amyloidogenic character of the CTDs of NPM1c+. Herein, with the aim of exploiting these conformational features, novel therapeutic strategies are proposed that rely on the induction of the selective self-cytotoxicity of leukemic blasts by focusing on agents such as peptides, peptoids or small molecules able to enhance amyloid aggregation and targeting selectively AML-NPM1c+ mutations.
Protein-protein interactions (PPIs) play critical roles in a wide range of biological processes including the dysregulation of cellular pathways leading to the loss of cell function, which in turn ...leads to diseases. The dysfunction of several signaling pathways is linked to the insurgence of pathological processes such as inflammation, cancer development and neurodegeneration. Thus, there is an urgent need for novel chemical modulators of dysregulated PPIs to drive progress in targeted therapies. Several PPIs have been targeted by bioactive compounds, and, often, to properly cover interacting protein regions and improve the biological activities of modulators, a particular focus concerns the employment of macrocycles as proteomimetics. Indeed, for their physicochemical properties, they occupy an intermediate space between small organic molecules and macromolecular proteins and are prominent in the drug discovery process. Peptide macrocycles can modulate fundamental biological mechanisms and here we will focus on peptidomimetics active on the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways.
It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that ...monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced 'metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression.
At the end of December 2019, an epidemic form of respiratory tract infection now named COVID-19 emerged in Wuhan, China. It is caused by a newly identified viral pathogen, the severe acute ...respiratory syndrome coronavirus (SARS-CoV-2), which can cause severe pneumonia and acute respiratory distress syndrome. On January 30, 2020, due to the rapid spread of infection, COVID-19 was declared as a global health emergency by the World Health Organization. Coronaviruses are enveloped RNA viruses belonging to the family of Coronaviridae, which are able to infect birds, humans and other mammals. The majority of human coronavirus infections are mild although already in 2003 and in 2012, the epidemics of SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERS-CoV), respectively, were characterized by a high mortality rate. In this regard, many efforts have been made to develop therapeutic strategies against human CoV infections but, unfortunately, drug candidates have shown efficacy only into
studies, limiting their use against COVID-19 infection. Actually, no treatment has been approved in humans against SARS-CoV-2, and therefore there is an urgent need of a suitable vaccine to tackle this health issue. However, the puzzled scenario of biological features of the virus and its interaction with human immune response, represent a challenge for vaccine development. As expected, in hundreds of research laboratories there is a running out of breath to explore different strategies to obtain a safe and quickly spreadable vaccine; and among others, the peptide-based approach represents a turning point as peptides have demonstrated unique features of selectivity and specificity toward specific targets. Peptide-based vaccines imply the identification of different epitopes both on human cells and virus capsid and the design of peptide/peptidomimetics able to counteract the primary host-pathogen interaction, in order to induce a specific host immune response. SARS-CoV-2 immunogenic regions are mainly distributed, as well as for other coronaviruses, across structural areas such as spike, envelope, membrane or nucleocapsid proteins. Herein, we aim to highlight the molecular basis of the infection and recent peptide-based vaccines strategies to fight the COVID-19 pandemic including their delivery systems.
Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor ...cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2
mice, an effect mimicked by CD8
T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8
T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression.
Protein-protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs) are involved in ...cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few "hot spots", thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.
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•The G-rich regions of telomeres are hotspots for oxidation which is handled by BER pathway.•Ape1 exerts an important role in telomeric physiology, but molecular details are ...lacking.•Acetylatable lysine residues on the N-sequence of Ape1 modulate the enzymatic processing of telomeric substrates.•NPM1 plays a role in modulating telomere length and Ape1 activity at abasic G4 structures.•Our data shed new light on the dynamics of Ape1 enzymatic activity at telomeres.
Loss of telomeres stability is a hallmark of cancer cells. Exposed telomeres are prone to aberrant end-joining reactions leading to chromosomal fusions and translocations. Human telomeres contain repeated TTAGGG elements, in which the 3′ exposed strand may adopt a G-quadruplex (G4) structure. The guanine-rich regions of telomeres are hotspots for oxidation forming 8-oxoguanine, a lesion that is handled by the base excision repair (BER) pathway. One key player of this pathway is Ape1, the main human endonuclease processing abasic sites. Recent evidences showed an important role for Ape1 in telomeric physiology, but the molecular details regulating Ape1 enzymatic activities on G4-telomeric sequences are lacking. Through a combination of in vitro assays, we demonstrate that Ape1 can bind and process different G4 structures and that this interaction involves specific acetylatable lysine residues (i.e. K27/31/32/35) present in the unstructured N-terminal sequence of the protein. The cleavage of an abasic site located in a G4 structure by Ape1 depends on the DNA conformation or the position of the lesion and on electrostatic interactions between the protein and the nucleic acids. Moreover, Ape1 mutants mimicking the acetylated protein display increased cleavage activity for abasic sites. We found that nucleophosmin (NPM1), which binds the N-terminal sequence of Ape1, plays a role in modulating telomere length and Ape1 activity at abasic G4 structures. Thus, the Ape1 N-terminal sequence is an important relay site for regulating the enzyme’s activity on G4-telomeric sequences, and specific acetylatable lysine residues constitute key regulatory sites of Ape1 enzymatic activity dynamics at telomeres.
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