Lorenzo Stella

• PhD
• Università degli Studi di Roma "Tor Vergata" at University of Rome Tor Vergata

Significance Bacterial drug resistance is a crucial threat to global health, and antimicrobials with novel mechanisms of action are urgently needed. Antimicrobial peptides are natural molecules that kill bacteria mostly by perturbing their membranes, and they constitute promising compounds for fighting resistant microbes. Their activity is normally...

SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associated with different rare diseases and hematologic malignancies, and recent studies have individuated SHP2 as a central node in oncogenesis and cancer dru...

Antimicrobial peptides (AMPs) selectively kill bacteria by disrupting their cell membranes, and are promising compounds to fight drug-resistant microbes. Biophysical studies on model membranes have characterized AMP/membrane interactions and the mechanism of bilayer perturbation, showing that accumulation of cationic peptide molecules in the extern...

Antimicrobial peptides (AMPs) attack bacterial membranes selectively, killing microbes at concentrations that cause no toxicity to the host cells. This selectivity is not due to interaction with specific receptors but is determined by the different lipid compositions of the membranes of the two cell types and by the peculiar physicochemical propert...

Host-defense peptides (HPDs) are bactericidal and immunomodulatory molecules, part of the innate immune system of many organisms, including man. They kill bacteria mostly by perturbing their membranes, and for this reason they are a promising class of molecules to fight drug-resistant microbes. However, their success towards clinical application is...

The vacuolar H⁺-ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic...

Staphylococcus aureus, a bacterium resistant to multiple drugs, is a significant cause of illness and death worldwide. Antimicrobial peptides (AMPs) provide an excellent potential strategy to cope with this threat. Recently, we characterized a derivative of the frog-skin AMP esculentin-1a, Esc(1–21) (1) that is endowed with potent activity against...

Many biological functions are mediated by protein-protein interactions (PPIs), often involving specific structural modules, such as SH2 domains. Inhibition of PPIs is a pharmaceutical strategy of growing importance. However, a major challenge in the design of PPI inhibitors is the large interface involved in these interactions, which, in many cases...

Fluorescence anisotropy (or polarization) is a powerful technique to study biomolecular association processes, by following the rotational motions of one of the two partners in the interaction, labeled with a fluorophore. It can be used to determine dissociation constants in solution, down to nM values, and unlabeled ligands can be characterized, t...

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight antibiotic-resistant infections. In most cases, they kill bacteria by making their membrane permeable and therefore exhibit low propensity to induce bacterial resistance. In addition, they are often selective, killing bacteria at concentrations lower than those at which...

Antimicrobial peptides (AMPs) represent a promising class of compounds to fight resistant infections. They are commonly thought to kill bacteria by perturbing the permeability of their cell membranes. However, bacterial killing requires a high coverage of the cell surface by bound peptides, at least in the case of cationic and amphipathic AMPs. The...

Peptidomimetic antimicrobials exhibit a selective interaction with bacterial cells over mammalian cells once they have achieved an optimum amphiphilic balance (hydrophobicity/hydrophilicity) in the molecular architecture. To date, hydrophobicity and cationic charge have been considered the crucial parameters to attain such amphiphilic balance. Howe...

(1) Background: antimicrobial resistance is becoming a dramatic problem for public health, and the design of new antimicrobial agents is an active research area. (2) Methods: based on our previous work, we designed an improved version of the crabrolin peptide and characterized its functional and structural properties with a wide range of techniques...

Membrane-active small molecules (MASMs) are small organic molecules designed to reproduce the fundamental physicochemical properties of natural antimicrobial peptides: their cationic charge and amphiphilic character. This class of compounds has a promising broad range of antimicrobial activity and, at the same time, solves some major limitations of...

Antimicrobial peptides (AMPs) are natural molecules, produced by all organisms as a defense against infections. They usually kill pathogens by perturbing the permeability of their cell membranes. Due to this mechanism, AMPs exhibit a low propensity to induce bacterial resistance and are therefore promising compounds to fight antibiotic-resistant in...

A chemoselective photocatalytic system to perform thioether oxidation to sulfoxide is presented. The light-induced oxidation process is here promoted by a metal-free quinoid catalyst, namely 1-hexylKuQuinone (KuQ). Reactions performed in a fluorinated solvent (i.e., HFIP), using O2 as the oxidant, at room temperature, lead to complete thioanisole c...

The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain...

We developed a new class of inhibitors of protein–protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-assoc...

The development of artificial vesicles into responsive architectures capable of sensing the biological environment and simultaneously signaling the presence of a specific target molecule is a key challenge in a range of biomedical applications from drug delivery to diagnostic tools. Herein, the rational design of biomimetic DNA‐grafted quatsome (QS...

Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl−/H+ exchangers f...

Mutations of PTPN11, the gene coding for the Src homology 2 domain-containing phosphatase 2 (SHP2), cause childhood leukemias and developmental disorders. SHP2 inhibitors targeting the catalytic site or an allosteric pocket lack specificity or are ineffective on pathogenic variants. In addition, several data indicate that increased association with...

The activity of many antibiotics depends on the initial density of cells used in bacteria growth inhibition assays. This phenomenon, termed the inoculum effect, can have important consequences for the therapeutic efficacy of the drugs, since bacterial loads vary by several orders of magnitude in clinically relevant infections. Antimicrobial peptide...

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorder...

SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associated with different rare diseases and hematologic malignancies, and recent studies have individuated SHP2 as a central node in oncogenesis and cancer dru...

Germline PTPN11 mutations cause Noonan syndrome (NS), the most common disorder among RASopathies. PTPN11 encodes SHP2, a protein tyrosine‐phosphatase controlling signaling through the RAS‐MAPK and PI3K‐AKT pathways. Generally, NS‐causing PTPN11 mutations are missense changes destabilizing the inactive conformation of the protein or enhancing its bi...

Objective: To investigate the molecular cause(s) underlying a severe form of infantile-onset parkinsonism and characterize functionally the identified variants. Methods: A trio-based whole exome sequencing (WES) approach was used to identify the candidate variants underlying the disorder. In silico modeling, and in vitro and in vivo studies were...

Host defense peptides selectively kill bacterial and cancer cells (including those that are drug-resistant) by perturbing the permeability of their membranes, without being significantly toxic to the host. Coulombic interactions between these cationic and amphipathic peptides and the negatively charged membranes of pathogenic cells contribute to th...

Trichogin GA IV is a short peptaibol with antimicrobial activity. This uncharged, but amphipathic, sequence is aligned at the membrane interface and undergoes a transition to an aggregated state that inserts more deeply into the membrane, an assembly that predominates at a peptide‐to‐lipid ratio (P/L) of 1:20. In this work, the natural trichogin se...

Trichogin is a natural peptide endowed with antimicrobial and antitumor activity. A member of the peptaibol family, trichogin possesses a C‐terminal amino alcohol. In the past, this moiety was substituted for a methyl ester for synthetic purposes and it was observed that this apparently slight modification caused significant changes in the peptide...

Neutrophils are key components of the innate arm of the immune system and represent the frontline of host defense against intruding pathogens. However, neutrophils can also cause damage to the host. Nanomaterials are being developed for a multitude of different purposes and these minute materials may find their way into the body through deliberate...

A synthetic antimicrobial peptide library based on the human autophagy 16 polypeptide has been developed. Designed acetylated peptides bearing lipids of different chain lengths, resulted in peptides with enhanced potency compared to the parent Atg16. A 21-residue fragment of Atg16 conjugated to 4–methylhexanoic acid (K30) emerged as the most potent...

Tumor angiogenesis, essential for cancer development, is regulated mainly by vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which are overexpressed in cancer cells. Therefore, the VEGF/VEGFR interaction represents a promising pharmaceutical target to fight cancer progression. The VEGF surface interacting with VEGFRs compr...

References in scientific papers play an important role in acknowledging prior work of others on the topic under investigation. Moreover, they are used to show the research is built on solid ground, carefully prepared by others. However, proper citation requires that one has read and understood the paper that is cited. We discuss an example of one o...

Aberrant activation or inhibition of potassium (K+) currents across the plasma membrane of cells has been causally linked to altered neurotransmission, cardiac arrhythmias, endocrine dysfunction, and (more rarely) perturbed developmental processes. The K+ channel subfamily K member 4 (KCNK4), also known as TRAAK (TWIK-related arachidonic acid-stimu...

Human serum albumin (HSA) is characterized by 17 disulfides and by only one un‐paired cysteine (Cys34), which can be free in the reduced albumin or linked as a mixed disulfide with cysteine, or in minor amount with other natural thiols, in the oxidized albumin. In healthy subjects, the level of the oxidized form is about 35%, but it rises up to 70%...

A novel type of graphene-like nanoparticle, synthesized by oxidation and unfolding of C60 buckminsterfullerene fullerene, showed multiple and reproducible sensitivity to Cu2+, Pb2+, Cd2+, and As(III) through different degrees of fluorescence quenching or, in the case of Cd2+, through a remarkable fluorescence enhancement. Most importantly, only for...

Here we report the design of membrane-active peptidomimetic molecules with tunable arrangement of hydrophobic and polar groups. Inspite of the same chemical composition, the effective hydrophobicities of the compounds were different as a consequence of their chemical structure and conformational properties. The compound with a lower effective hydro...

Selective targeting is a crucial property of nanocarriers used for drug delivery in cancer therapy. We generated biotinylated octahedral DNA nanocages functionalized with folic acid through bio-orthogonal conjugation chemistry. Molecular modelling indicated that a distance of about 2.5 nm between folic acid and DNA nanocage avoids steric hindrance...

Carbon-based nanomaterials including carbon nanotubes (CNTs) have been shown to trigger inflammation. However, how these materials are 'sensed' by immune cells is not known. Here we compared the effects of two carbon-based nanomaterials, single-walled CNTs (SWCNTs) and graphene oxide (GO), on primary human monocyte-derived macrophages. Genome-wide...

Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment...

Alport syndrome is a rare hereditary disorder caused by rare variants in 1 of 3 genes encoding for type IV collagen. Rare variants in COL4A5 on chromosome Xq22 cause X-linked Alport syndrome, which accounts for ∼80% of the cases. Alport syndrome has a variable clinical presentation, including progressive kidney failure, hearing loss, and ocular def...

In this work, an extensive set of spectroscopic and biophysical techniques (including FT-IR absorption, CD, 2D-NMR, fluorescence, and CW/PELDOR EPR) was used to study the conformational preferences, membrane interaction, and bioactivity properties of the naturally occurring synthetic 14-mer peptaibiotic chalciporin A, characterized by a relatively...

We propose a simple and efficient strategy to significantly improve the antibacterial activity of peptaibols and other antimicrobial peptides by N-terminal capping with 1,2,3-triazole bearing various hydrophobic substituents on C-4. We showed, herein, that such N-terminal insertions on alamethicin F50/5 could enhance its antimicrobial activity on g...

Temporin L (TempL) is a 13 residue Host Defense Peptide (HDP) isolated from the skin of frogs. It has a strong affinity for lipopolysaccharides (LPS), which is related to its high activity against Gram-negative bacteria and also to its strong tendency to neutralize the pro-inflammatory response caused by LPS release from inactivated bacteria. A des...

On the cover: The cover image, by Luca Pannone et al., is based on the Research Article Structural, Functional, and Clinical Characterization of a Novel PTPN11 Mutation Cluster Underlying Noonan Syndrome, Pages 451–459. DOI 10.1002/humu.23175

Context: The nitrobezoxadiazole derivative NBDHEX is a potent inhibitor of glutathione transferase P1-1 (GSTP1-1) endowed with outstanding anticancer activity in different tumor models. Objective: To characterize by in vitro biochemical and in silico studies the NBDHEX analogues named MC2752 and MC2753. Materials and methods: Synthesis of MC2752 an...

Germline mutations in PTPN11, the gene encoding the Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2), cause Noonan syndrome (NS), a relatively common, clinically variable, multisystem disorder. Here, we report on the identification of five different PTPN11 missense changes affecting residues Leu(261) , Leu(262) and Arg(265...

Host-defense peptides (HDPs) are promising compounds against multidrug-resistant microbes. In vitro, their bactericidal and toxic concentrations are significantly different, but this might be due to the use of separate assays, with different cell-densities. For experiments with a single cell-type, the cell-density dependence of the active concentra...

In this paper we propose a new mathematical model to describe the mechanisms of biological macromolecules interactions. Our model consists of a discrete stationary random sequence given by a solution of difference stochastic equation, characterized by a drift predictive component and by a diffusion term. The relative statistical estimations are ver...

α‐actinin‐4 gene (ACTN4) mutations cause a form of kidney injury called familial focal segmental glomerulosclerosis (FSGS) in humans. Individuals who carry disease‐causing ACTN4 mutations initially present with proteinuria due to podocyte injury, and many eventually develop end stage kidney disease. The disease‐causing ACTN4 mutations are exclusive...

Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain at...

In this study, several proteins (albumin, lysozyme, insulin) and model compounds (Trp, Tyr, homopolypeptides) were used to demonstrate the origin of the fluorescence observed upon their excitation at 220-230 nm. In the last 10 years we have observed a worrying increase in the number of articles claiming that this fluorescence originates from the pr...

The interaction of lipid environments with the type I' β-turn peptide structure called CSF114 and its N-glucosylated form CSF114(Glc), previously developed as a synthetic antigenic probe recognizing specific autoantibodies in a subpopulation of multiple sclerosis patients' serum, was investigated by fluorescence spectroscopy and electrochemical exp...

The RASopathies constitute a family of autosomal dominant disorders whose major features include facial dysmorphism, cardiac defects, reduced postnatal growth, variable cognitive deficits, ectodermal and skeletal anomalies, and susceptibility to certain malignancies. Noonan syndrome (NS), the commonest RASopathy, is genetically heterogeneous and ca...

Several diseases are related to the lack or to the defective activity of a particular enzyme and therefore these proteins potentially represent a very interesting class of therapeutics. However, their application is hampered by their rapid degradation and immunogenic side-effects. Most attempts to increase the bioavailability of therapeutic enzymes...

Total syntheses and complete characterizations of singly substituted PheCN -based analogs of alamethicin AlaP, which is active on model and natural membranes, and the TM peptide, which inserts in a trans-membrane orientation in lipid bilayers, are reported. The syntheses of the AlaP analogs were performed in solution, while those of TM and its anal...

Zimmermann-Laband syndrome (ZLS) is a developmental disorder characterized by facial dysmorphism with gingival enlargement, intellectual disability, hypoplasia or aplasia of nails and terminal phalanges, and hypertrichosis. We report that heterozygous missense mutations in KCNH1 account for a considerable proportion of ZLS. KCNH1 encodes the voltag...

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeuro...

Two analogs of the ten-amino acid residue, membrane-active lipopeptaibiotic trichogin GA IV, mono-labeled with 4-cyano-α-methyl-L-phenylalanine, a potentially useful fluorescence and IR absorption probe of the local microenvironment, were synthesized by the solid-phase methodology and conformationally characterized. The single modification was inco...

The synthetic LAH4 peptides were designed to investigate the interactions that determine the membrane topology of helical peptides (1). Their core consist of alanines, leucine and four histidines arranged to form an amphipathic helix, as well as two lysines at each terminus. Through protonation of its histidines (pKs between 5.4 and 6.0) the alignm...

Synchronous fluorescence spectra are performed by simultaneously scanning both the excitation and emission wavelengths, and are widely used to analyze complex mixtures of fluorophores, since they yield narrower bands than traditional excitation or emission spectra. Many recent studies claim that synchronous spectra are able to separate tryptophan (...

Determining the structure of membrane-active peptides inside lipid bilayers is essential to understand their mechanism of action. Molecular dynamics simulations can easily provide atomistic details, but need experimental validation. We assessed the reliability of self-assembling (or "minimum-bias") and potential of mean force (PMF) approaches, usin...

Antimicrobial peptides (AMPs) kill bacteria mainly through the perturbation of their membranes and are promising compounds to fight drug-resistance. Models of the mechanism of AMPs-induced membrane perturbation were developed based on experiments in liposomes, but their relevance for bacterial killing is debated. We determined the association of an...

Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutat...

Myhre syndrome (MYHRS, OMIM 139210) is an autosomal dominant disorder characterized by developmental and growth delay, athletic muscular built, variable cognitive deficits, skeletal anomalies, stiffness of joints, distinctive facial gestalt and deafness. Recently, SMAD4 (OMIM 600993) was identified by exome sequencing as the disease gene mutated in...

Trichogin GA IV, an antimicrobial peptaibol, exerts its function by augmenting membrane permeability, but the molecular aspects of its pore-forming mechanism are still debated. Several lines of evidence indicate a ‘barrel-stave’ channel structure, similar to that of alamethicin, but the length of a trichogin helix is too short to span a normal bila...

stella@stc.uniroma2.it Antimicrobial peptides (AMPs) constitute the first defense line of most organisms against a wide range of pathogens. In contrast to common antibiotics, the main target of AMPs is the cell membrane: these peptides perturb the permeability of the plasma membrane, leading to loss of intracellular materials and cell death. Bacter...

RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Va...

FSGS is characterized by the presence of partial sclerosis of some but not all glomeruli. Studies of familial FSGS have been instrumental in identifying podocytes as critical elements in maintaining glomerular function, but underlying mutations have not been identified for all forms of this genetically heterogeneous condition. Here, exome sequencin...

Antimicrobial peptides (AMPs) are promising compounds for developing new antibiotic drugs against drug-resistant bacteria. Many of them kill bacteria by perturbing their membranes but exhibit no significant toxicity towards eukaryotic cells. The identification of the features responsible for this selectivity is essential for their pharmacological d...

Glutathione transferases (GSTs) are protection enzymes capable of conjugating glutathione (GSH) to toxic compounds. During evolution an important catalytic cysteine residue involved in GSH activation was replaced by serine or, more recently, by tyrosine. The utility of these replacements represents an enigma because they yield no improvements in th...

The aggregation propensity of helical oligopeptides formed exclusively by the conformationally constrained α-aminoisobutyric acid (Aib or U in a three- or single-letter code, respectively) was studied in methanol and methanol/water solutions by spectroscopic methods (UV-Vis absorption, steady-state and time-resolved fluorescence, FT-IR absorption)...