Marco GobbiMario Negri Institute for Pharmacological Research | Mario Negri · Department of Molecular Biochemistry and Pharmacology
Marco Gobbi
Head, Laboratory of Pharmacodynamics and Pharmacokinetics
About
276
Publications
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Introduction
For a description of the current research activities see:
https://www.marionegri.it/laboratories/laboratory-of-pharmacodynamics-and-pharmacokinetics
Co−author in >190 scientific publications on international journals with peer-review. First or last author in >65 of these publications.
https://www.scopus.com/authid/detail.uri?authorId=35423680800
H-Index at February 2024: 47 (Scopus)
Member of the Editorial Board of the Journal of Biological Chemistry and Scientific Reports
Skills and Expertise
Additional affiliations
September 1985 - present
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Position
- Principal Investigator
Description
- Research activities: www.marionegri.it/en_US/home/research_en/dipartimenti_en/molecular_biochemistry_and_pharmacology/pharmacodynamics_and_pharmacokinetics Publications: www.experts.scival.com/moh-it/expertPubs.asp?n=Marco+Gobbi&u_id=11840&oe_id=1&o_id=70
Publications
Publications (276)
Background: A oligomers are major players in Alzheimer disease, but the tools for their detection are not satisfactory. Results: We developed a SPR-based immunoassay and a test in C. elegans, specifically identifying toxic oligomers. Conclusion: These methods allow study of the effects of mutations or drugs on A oligomerization. Significance: The S...
A growing number of important human diseases are associated with the aggregation and deposition of incorrectly folded proteins in the form of highly structured amyloid fibrils. The aggregation process involves the formation of intermediate oligomeric assemblies with toxic properties. There are many commonalities among the different amyloid diseases...
Great interest is currently being devoted to the development of nanoparticles (NPs) for biomedical purposes, designed to improve the pharmacokinetic profile of their cargos (either imaging probes or drugs) and to enhance the specific targeting at the disease site. Recent works suggest that Surface Plasmon Resonance (SPR), widely used for the analys...
Chimeric antigen receptor (CAR) T cells represent a revolutionary immunotherapy that allows specific tumor recognition by a unique single-chain fragment variable (scFv) derived from monoclonal antibodies (mAbs). scFv selection is consequently a fundamental step for CAR construction, to ensure accurate and effective CAR signaling toward tumor antige...
Mannose-binding lectin (MBL) activates the complement system lectin pathway and subsequent inflammatory mechanisms. The incidence and outcome of many human diseases, such as brain ischemia and infections, are associated with and influenced by the activity and serum concentrations of MBL in body fluids. To quantify MBL levels, tests based on ELISA a...
There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. We previously found that the PERK kinase inhibitor GSK2606414 delayed cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GS...
: We designed, produced, and purified a novel IgG1-like, bispecific antibody (bsAb) directed against B-cell maturation antigen (BCMA), expressed by multiple myeloma (MM) cells, and an immune checkpoint inhibitor (ICI), PDL1, expressed in the MM microenvironment. The BCMAxPDL1 bsAb was fully characterized in vitro. BCMAxPDL1 bound specifically and s...
Selenoprotein N (SEPN1) is a protein of the endoplasmic reticulum (ER) whose inherited defects originate SEPN1-related myopathy (SEPN1-RM). Here, we identify an interaction between SEPN1 and the ERstress-induced oxidoreductase ERO1A. SEPN1 and ERO1A, both enriched in mitochondria-associated membranes (MAMs), are involved in the redox regulation of...
We developed and validated a technology platform for designing and testing peptides inhibiting the infectivity of SARS-CoV-2 spike protein-based pseudoviruses. This platform integrates target evaluation, in silico inhibitor design, peptide synthesis, and efficacy screening. We generated a cyclic peptide library derived from the receptor-binding dom...
Background:
The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome, through genetic deletion of the rate-limiting enzyme of the pathway...
Prions are deadly infectious agents made of PrPSc, a misfolded variant of the cellular prion protein (PrPC) which self-propagates by inducing misfolding of native PrPC. PrPSc can adopt different pathogenic conformations (prion strains), which can be resistant to potential drugs, or acquire drug resistance, hampering the development of effective the...
Aim
The effect of liposomes bi-functionalized with phosphatidic acid and with a synthetic peptide derived from human apolipoprotein E has been evaluated on the aggregation features of different amyloidogenic proteins: human Amyloid β1–40 (Aβ1–40), transthyretin (TTR) variant S52P, human β2microglobulin (β2m) variants ΔN6 and D76N, Serum Amyloid A (...
Gelsolin amyloidosis (AGel) is characterized by multiple systemic and ophthalmic features resulting from pathological tissue deposition of the gelsolin (GSN) protein. To date, no cure is available for the treatment of any form of AGel. More than ten single-point substitutions in the GSN gene are responsible for the occurrence of the disease and, am...
Biological medicines have improved patients’ outcomes, but their high costs may limit access. Biosimilars, alternatives that have demonstrated high similarity in terms of quality, safety, and efficacy to an already licensed originator biological product, could increase competition and decrease prices. Given the expanding number of biosimilars, pati...
N-glycosylation and disulfide bond formation are two essential steps in protein folding that occur in the endoplasmic reticulum (ER) and reciprocally influence each other. Here, to analyze crosstalk between N-glycosylation and oxidation, we investigated how the protein disulfide oxidase ERO1-alpha affects glycosylation of the angiogenic VEGF¹²¹, a...
Fingolimod is a sphingosine 1-phosphate-receptor modulator approved for the oral treatment of relapsing–remitting multiple sclerosis (RRMS), a form of MS characterized by a pattern of exacerbation of neurological symptoms followed by recovery. Here, we validated a simple and rapid liquid chromatography–tandem mass spectrometry method for the measur...
The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to ob...
Circulating mannose-binding lectin (MBL) plays an important role in the progression of tissue damage caused by ischemic events, an account of its high-affinity, multivalent binding to carbohydrate arrays exposed on damaged endothelium (damage-associated molecular patterns, DAMPS). MBL inhibitors have therefore been proposed as a novel protective th...
High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants...
The monitoring of the blood levels of therapeutic antibodies and their immune responses is proposed to guide and optimize therapy with these expensive drugs. We describe a novel Surface Plasmon Resonance (SPR)-based assay suitable for the simultaneous determination of serum concentrations of infliximab and anti-infliximab antibodies. The real-time...
Background
Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (en...
Background
Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out‐of‐hospital CA. He...
Polyethylene glycol, used as a stabilizer in nanomedicine formulations, has recently been indicated as the possible cause of the anaphylactic reactions against the COVID-19 mRNA-based vaccines, but the evidence supporting this is contradictory, and other factors might be involved.
Gelsolin comprises six homologous domains, named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease causing progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Although several different amyloidogenic variants of gelsolin have been identified, only the most common mutan...
The multidomain protein gelsolin (GSN) is composed of six homologous modules, sequentially named G1 to G6. Single point substitutions in this protein are responsible for AGel amyloidosis, a hereditary disease characterized by progressive corneal lattice dystrophy, cutis laxa, and polyneuropathy. Several different amyloidogenic variants of GSN have...
The rapid spread of the pandemic caused by the SARS-CoV-2 virus has created an unusual situation, with rapid searches for compounds to interfere with the biological processes exploited by the virus. Doxycycline, with its pleiotropic effects, including anti-viral activity, has been proposed as a therapeutic candidate for COVID-19 and about twenty cl...
Fatal familial insomnia (FFI) is a dominantly inherited prion disease linked to the D178N mutation in the gene encoding the prion protein (PrP). Symptoms, including insomnia, memory loss and motor abnormalities, appear around 50 years of age, leading to death within two years. No treatment is available. A ten-year clinical trial of doxycycline (dox...
The pandemic caused by the SARS-CoV-2 has created the need of compounds able to interfere with the biological processes exploited by the virus. Doxycycline, with its pleiotropic effects, including anti-viral activity, has been proposed as a therapeutic candidate for COVID-19 and about twenty clinical trials have started since the beginning of the p...
Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients...
The phytotherapeutic properties of Glycyrrhiza glabra (licorice) extract are mainly attributed to glycyrrhizin (GR) and glycyrrhetinic acid (GA). Among their possible pharmacological actions, the ability to act against viruses belonging to different families, including SARS coronavirus, is particularly important. With the COVID-19 emergency and the...
The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer’s disease (AD). Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, while plaques comprise fibrillar forms of amyloid-β (Aβ). Both form toxic oligomers during aggregation, and are thought to interact synergist...
Solid tumors are often characterized by a hypoxic microenvironment which contributes, through the hypoxia-inducible factor HIF-1, to the invasion-metastasis cascade. Endoplasmic reticulum (ER) stress also leads tumor cells to thrive and spread by inducing a transcriptional and translational program, the Unfolded Protein Response (UPR), aimed at res...
C1 esterase inhibitor (C1INH) is known to exert its inhibitory effect by binding to several target proteases of the contact and complement systems. One of C1INH’s targets comprise mannose-binding lectin (MBL), a critical player in post-stroke pathophysiology. We therefore explored the effects of recombinant human (rh) and plasma derived (pd) C1INH...
Background
The genetically engineered, humanized, bispecific monoclonal antibody emicizumab (Hemlibra®) that mimics the cofactor activity of activated FVIII has been approved for treatment of haemophilia A patients with and without inhibitor. In the pivotal pre‐marketing clinical trials emicizumab prophylaxis significantly reduced bleeding rates co...
Background
Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest.
Methods and Results
Cardiac arrest was ischemically induced in 36 pi...
Dysregulation of the complement system is central to age-related macular degeneration (AMD), the leading cause of blindness in the developed world. Most of the genetic variation associated with AMD resides in complement genes, with the greatest risk associated with polymorphisms in the complement factor H ( CFH ) gene; factor H (FH) is the major in...
Different lines of evidence indicate that monitoring the blood levels of therapeutic antibodies, characterized by high inter-individual variability, can help to optimize clinical decision making, improving patient outcomes and reducing costs with these expensive treatments. A surface plasmon resonance (SPR)-based immunoassay has recently been shown...
The current pharmacological treatment of Huntington’s disease (HD) is palliative, and therapies to restore functions in patients are needed. One of the pathways affected in HD involves brain cholesterol (Chol) synthesis, which is essential for optimal synaptic transmission. Recently it was reported that in a HD mouse model, the delivery of exogenou...
The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s ant...
Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet e...
α-Synuclein oligomers are crucial players in the pathogenesis of Parkinson's disease. Some mechanisms involved in α-synuclein oligomer detrimental effects include membrane damage, neuroinflammation and protein-protein interactions. Recently, the cellular prion protein (PrPC) emerged as an interactor of α-synuclein oligomers, apparently mediating th...
Repurposing doxycycline for the treatment of amyloidosis has recently been put forward because of the antiaggregating and anti-inflammatory properties of the drug. Most of the investigations of the therapeutic potential of doxycycline for neurodegenerative amyloidosis, e.g., prion and Alzheimer disease (AD), have been carried out in mouse models, b...
It is increasingly acknowledged that an important number of human diseases are associated with the aggregation of incorrectly folded peptide/proteins, in the form of insoluble deposits of fibrillar species (amyloids). During the early stages of this process, very reactive oligomeric intermediates are formed which are often more toxic than the end‐s...
β-Amyloid oligomers (AβOs) and neuroinflammation are 2 main culprits to counteract in Alzheimer's disease (AD). Doxycycline (DOXY) is a second generation antibiotic of the tetracycline class that are promising drugs tested in many clinical trials for a number of different pathologies. DOXY is endowed with antiamyloidogenic properties and better cro...
3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injectio...
Prion diseases are neurodegenerative conditions characterized by the conformational conversion of the cellular prion protein (PrPC), an endogenous membrane glycoprotein of uncertain function, into PrPSc, a pathological isoform that replicates by imposing its abnormal folding onto PrPC molecules. A great deal of evidence supports the notion that PrP...
Intrinsic cytotoxicity of CPZ.
HEK293 cells stably expressing WT (A) or EGFP- (B) PrP were treated with increasing concentrations of CPZ (0.3–10 μM), TP (10 μM) or vehicle (VCH) controls for 3 48 h. Cell viability was then estimated by MTT assay. Bars represent mean values of four (n = 4)independent experiments (± standard error). No statistical di...
Trabectedin and its analogue lurbinectedin are effective drugs used in the treatment of ovarian cancer. Since the presence of ascites is a frequent event in advanced ovarian cancer we asked the question whether ascites could modify the activity of these compounds against ovarian cancer cells. The cytotoxicity induced by trabectedin or lurbinectedin...
Background:
Traditional quantitative structure - property / activity relationships (QSPRs/QSARs) are based on representation of molecular structure by molecular graph or simplified molecular input-line entry system (SMILES). It is attractive idea to develop predictive models for large molecules in general and for peptides in particular. However, t...
Background and objective:
Predicting blood-brain barrier permeability for novel compounds is an important goal for neurotherapeutics-focused drug discovery. It is impossible to determine experimentally the blood-brain barrier partitioning of all possible candidates. Consequently, alternative evaluation methods based on computational models are des...
Multi-therapies are common in clinical practice. It is well known that alterations of CYP-mediated drug metabolism by simultaneous administration of other drugs is one of the most common causes of drug-drug interactions. Using in-silico methods derived from network analysis, and based on available data about the CYP-mediated drug metabolism and the...
Para-methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity, whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated an HPLC-MS/MS method to measure the compound's concentrations in plasma, and applied it to describe the pharmacokinetic properties after...
The 24-residue peptide humanin (HN) has been proposed as peptide-based inhibitors able to interact directly with amyloid-β (Aβ) oligomers and interfere with the formation and/or biological properties of toxic Aβ species. When administered exogenously HN, or its synthetic S14G-derivative (HNG), exerted multiple cytoprotective effects, counteracting...
Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer’s disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from to...
4-methyl-5-(4-methylphenyl)-4,5-dihydrooxazol-2-amine (4,4’-DMAR) is an analog of the psychostimulants 4-methylaminorex and aminorex, recently added to the schedule II of 1971 Convention on Psychotropic Substances. No information is available about the drug’s pharmacokinetic profile and its metabolites. In the present study, metabolism profilers av...
DMAR is an analog of the known psychostimulants 4-methylaminorex and aminorex. In the light of reports of deaths associated with its abuse, and the easy access from Internet vendors, the EU Council recently decided on control measures across Member States. Here we describe a validated method for measuring plasma levels of cis-4,4′-DMAR, crucial for...
15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42, an aggregating peptide implicated in the pathogenesis of Alzheimer's disease (AD). The 15B3 antibody: i) inhibits the bindin...
• The new psychoactive drugs (NPS) are a wide series of new substances that have been designed to mimick the psychotropic effect of traditional illicit drugs [Council Decision 2005/387/JHA of 20 May 2005]. • The principal problem of these substances is that they are not controlled by national drug laws and manufacturers of these compounds replace f...
• The new psychoactive drugs (NPS) are a wide series of new substances that have been designed to mimicking the psychotropic effect of traditional illicit drugs (Council Decision 2005/387/JHA). • The most obvious problem of these substances is that they are not controlled by national drug law and manufacturers of these compounds replace functional...