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1. Analysis of Patients’ Characteristics and Treatment Profile of People Who Use Drugs (PWUDs) with and without a Co-Diagnosis of Viral Hepatitis C: A Real-World Retrospective Italian Analysis

Author

Nava FA, Mangia A, Riglietta M, Somaini L, Foschi FG, Claar E, Maida I, Ucciferri C, Frigerio F, Hernandez C, Dovizio M, Perrone V, Degli Esposti L, and Puoti M

Subjects
drug abuse, hepatitis c virus, alcohol dependency, real-world evidence, Therapeutics. Pharmacology, RM1-950
Abstract

Felice Alfonso Nava,1 Alessandra Mangia,2 Marco Riglietta,3 Lorenzo Somaini,4 Francesco Giuseppe Foschi,5 Ernesto Claar,6 Ivana Maida,7 Claudio Ucciferri,8 Francesca Frigerio,9 Candido Hernandez,10 Melania Dovizio,11 Valentina Perrone,11 Luca Degli Esposti,11 Massimo Puoti12 1U.O. Sanità Penitenziaria e Area Dipendenze, Azienda ULSS 6 Euganea, Padova, Italy; 2UOS Epatologia, Istituto di Ricovero e Cura “Casa Sollievo della Sofferenza”, S. Giovanni Rotondo, Italy; 3UOC Dipendenze, ASST Papa Giovanni XXIII, Bergamo, Italy; 4Servizio per le Dipendenze, SERT di Cossato, Biella, Italy; 5UOC Medicina Interna, Ospedale di Faenza, Faenza, Italy; 6UOC Medicina Interna, Ospedale Evangelico “Villa Betania”, Napoli, Italy; 7UOC Malattie Infettive e Parassitarie, Azienda Ospedaliero Universitaria di Sassari, Sassari, Italy; 8Clinica di Malattie Infettive Ospedale “SS Annunziata”, Chieti, Italy; 9Gilead Sciences, Milano, Italy; 10Gilead Sciences, Global Medical Affairs, Stockley Park, London, UB11 1BD, UK; 11CliCon S.R.L. Società Benefit, Health Economics and Outcomes Research, Bologna, Italy; 12SC Malattie Infettive, ASST Grande Ospedale Metropolitano Niguarda, Milano, ItalyCorrespondence: Luca Degli Esposti, CliCon S.r.l. Società Benefit, Health, Economics & Outcomes Research, Via Murri, 9, Bologna, 40137, Italy, Tel +39 544 38393, Fax +39 544 212699, Email luca.degliesposti@clicon.itPurpose: Hepatitis C virus (HCV) spreads from contact with blood of an infected person. HCV infections are common among people who use drugs (PWUDs), when sharing needles, syringes, or other equipment for injected drugs. The advent of pangenotypic direct-antiviral agents (DAA) in 2017 transformed the treatment landscape for HCV, but PWUDs remain a complex and hard-to-treat population with high risk of HCV reinfection. The aim of this real-world analysis was to characterize the demographic and clinical features of PWUDs in Italy, also focusing on comorbidity profile, treatment with DAAs, resource consumptions for the National Health System (NHS).Patients and Methods: During 01/2011– 06/2020, administrative databases of Italian healthcare entities, covering 3,900,000 individuals, were browsed to identify PWUDs with or without HCV infection. Among HCV+ patients, a further stratification was made into treated and untreated with DAAs. The date of PWUD or HCV first diagnosis or DAA first prescription was considered as index-date. Patients were then followed-up for one year. Alcohol-dependency was also investigated.Results: Total 3690 PWUDs were included, of whom 1141 (30.9%) PWUD-HCV+ and 2549 (69.1%) PWUD-HCV-. HCV-positive were significantly older (43.6 vs 38.5 years, p < 0.001), had a worse comorbidity profile (Charlson-index: 0.8 vs 0.4, p < 0.001), and high rates of psychiatric, respiratory, dermatological, musculoskeletal diseases and genitourinary (sexually transmitted) infections. Moreover, they received more drug prescriptions (other than DAAs, like anti-acids, antiepileptics, psycholeptics) and had undergone more frequent hospitalization, predominantly for hepatobiliary, respiratory system and mental disorders. DDA-untreated had significantly higher Charlson-index than DAA-treated (0.9 vs 0.6, p = 0.003). Alcoholism was found in 436 (11.8%) cases.Conclusion: This Italian real-world analysis suggests that PWUDs with HCV infection, especially those untreated with DAAs, show an elevated drug consumption due to their complex clinical profile. These findings could help to ameliorate the healthcare interventions on PWUDs with HCV infection.Keywords: drug abuse, hepatitis C virus, alcohol dependency, real-world evidence

Published
2023

2. Italian Real-World Analysis of the Impact of Polypharmacy and Aging on the Risk of Multiple Drug–Drug Interactions (DDIs) in HCV Patients Treated with Pangenotypic Direct-Acting Antivirals (pDAA)

Author

Fagiuoli S, Toniutto P, Coppola N, Ancona DD, Andretta M, Bartolini F, Ferrante F, Lupi A, Palcic S, Rizzi FV, Re D, Alvarez Nieto G, Hernandez C, Frigerio F, Perrone V, Degli Esposti L, and Mangia A

Subjects
administrative database, glecaprevir/pibrentasvir, hepatitis c, sofosbuvir/velpatasvir, polymedication, Therapeutics. Pharmacology, RM1-950
Abstract

Stefano Fagiuoli,1 Pierluigi Toniutto,2 Nicola Coppola,3 Domenica Daniela Ancona,4 Margherita Andretta,5 Fausto Bartolini,6 Fulvio Ferrante,7 Alessandro Lupi,8 Stefano Palcic,9 Francesca Vittoria Rizzi,10 Davide Re,11 Gema Alvarez Nieto,12 Candido Hernandez,13 Francesca Frigerio,14 Valentina Perrone,14 Luca Degli Esposti,14 Alessandra Mangia15 1Department of Medicine and Surgery, University of Milan Bicocca & Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy; 2Hepatology and Liver Transplantation Unit, Azienda Ospedaliero Universitaria, Udine, Italy; 3Infectious Diseases Unit, University of Campania L. Vanvitelli, Naples, Italy; 4Dipartimento Farmaceutico ASL BAT, Trani, Italy; 5UOC Assistenza Farmaceutica Territoriale, Azienda Ulss 8 Berica, Vicenza, Italy; 6Dipartimento Farmaceutico-Usl Umbria 2, Terni, Italy; 7Dipartimento Diagnostica Ed Assistenza Farmaceutica – ASL Frosinone, Frosinone, Italy; 8Struttura Complessa Di Cardiologia – ASL VCO, Omegna, Italy; 9Farmaceutica Territoriale- Azienda Sanitaria Universitaria Integrata Giuliano-Isontina (ASUGI), Trieste, Italy; 10UOS Farmacovigilanza e Monitoraggio Spesa Farmaceutica- ASL BAT, Trani, Italy; 11Servizio Farmaceutico Territoriale ASL Teramo, Teramo, Italy; 12Gilead Sciences, Medical Affairs Italy, Milan, Italy; 13Gilead Sciences, Global Medical Affairs, London, UK; 14Clicon S.r.l., Health Economics and Outcomes Research, Bologna, Italy; 15Gastroenterology and Transplant Hepatology, Papa Giovanni XXIII Hospital, Bergamo, 24127, ItalyCorrespondence: Luca Degli Esposti, CliCon S.r.l. Società Benefit, Health, Economics & Outcomes Research, Via Murri, 9, Bologna, 40137, Italy, Tel +390544 38393, Email luca.degliesposti@clicon.itPurpose: The study aims at investigating the impact of polymedication and aging in the prevalence of multiple drug-drug interactions (DDIs) on HCV patients treated with sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB).Patients and Methods: This is a retrospective analysis based on administrative data covering around 6.9 million individuals. Patients treated with SOF/VEL or GLE/PIB over November 2017–March 2020 were included. Index date corresponded to SOF/VEL or GLE/PIB first prescription during such period; patients were followed up for treatment duration. Analyses were then focused on patients with ≥ 2 comedications at risk of multiple DDIs. The severity and the effect of multiple DDI were identified using the Liverpool University tool.Results: A total of 2057 patients with SOF/VEL and 2128 with GLE/PIB were selected. Mean age of SOF/VEL patients was 58.5 years, higher than GLE/PIB ones (52.5 years) (p < 0.001), and patients > 50 years were more present in SOF/VEL vs GLE/PIB cohorts: 72% vs 58%, (p < 0.001). Most prescribed co-medications were cardiovascular, alimentary and nervous system drugs. Proportion of patients with ≥ 2 comedications was higher in SOF/VEL compared to GLE/PIB cohort (56.5% vs 32.3%, p < 0.001). Those at high-risk of multiple DDIs accounted for 11.6% (N = 135) of SOF/VEL and 19.6% (N = 135) of GLE/PIB (p < 0.001) patients with ≥ 2 comedications. Among them, the potential effect of DDI was a decrease of DAA serum levels (11% of SOF/VEL and GLE/PIB patients) and an increased concentration of comedication serum levels (14% of SOF/VEL and 42% of GLE/PIB patients).Conclusion: This real-world analysis provided a thorough characterization on the burden of polymedication regimens in HCV patients treated with SOF/VEL or GLE/PIB that expose such patients to an increased risk of DDIs. In our sample population, SOF/VEL regimen was more frequently detected on elderly patients and on those with ≥ 2 comedications at risk of multi-DDI, ie, among patients characterized by higher rates of comorbidities and polypharmacy.Keywords: administrative database, glecaprevir/pibrentasvir, hepatitis C, sofosbuvir/velpatasvir, polymedication

Published
2023

6. Italian Real-World Analysis of the Impact of Polypharmacy and Aging on the Risk of Multiple Drug–Drug Interactions (DDIs) in HCV Patients Treated with Pangenotypic Direct-Acting Antivirals (pDAA)

Author

Fagiuoli, S, Toniutto, P, Coppola, N, Ancona, D, Andretta, M, Bartolini, F, Ferrante, F, Lupi, A, Palcic, S, Rizzi, F, Re, D, Nieto, G, Hernandez, C, Frigerio, F, Perrone, V, Esposti, L, Mangia, A, Fagiuoli S., Toniutto P., Coppola N., Ancona D. D., Andretta M., Bartolini F., Ferrante F., Lupi A., Palcic S., Rizzi F. V., Re D., Nieto G. A., Hernandez C., Frigerio F., Perrone V., Esposti L. D., Mangia A., Fagiuoli, S, Toniutto, P, Coppola, N, Ancona, D, Andretta, M, Bartolini, F, Ferrante, F, Lupi, A, Palcic, S, Rizzi, F, Re, D, Nieto, G, Hernandez, C, Frigerio, F, Perrone, V, Esposti, L, Mangia, A, Fagiuoli S., Toniutto P., Coppola N., Ancona D. D., Andretta M., Bartolini F., Ferrante F., Lupi A., Palcic S., Rizzi F. V., Re D., Nieto G. A., Hernandez C., Frigerio F., Perrone V., Esposti L. D., and Mangia A.

Abstract

Purpose: The study aims at investigating the impact of polymedication and aging in the prevalence of multiple drug-drug interactions (DDIs) on HCV patients treated with sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB). Patients and Methods: This is a retrospective analysis based on administrative data covering around 6.9 million individuals. Patients treated with SOF/VEL or GLE/PIB over November 2017–March 2020 were included. Index date corresponded to SOF/VEL or GLE/PIB first prescription during such period; patients were followed up for treatment duration. Analyses were then focused on patients with ≥2 comedications at risk of multiple DDIs. The severity and the effect of multiple DDI were identified using the Liverpool University tool. Results: A total of 2057 patients with SOF/VEL and 2128 with GLE/PIB were selected. Mean age of SOF/VEL patients was 58.5 years, higher than GLE/PIB ones (52.5 years) (p < 0.001), and patients >50 years were more present in SOF/VEL vs GLE/PIB cohorts: 72% vs 58%, (p < 0.001). Most prescribed co-medications were cardiovascular, alimentary and nervous system drugs. Proportion of patients with ≥2 comedications was higher in SOF/VEL compared to GLE/PIB cohort (56.5% vs 32.3%, p < 0.001). Those at high-risk of multiple DDIs accounted for 11.6% (N = 135) of SOF/VEL and 19.6% (N = 135) of GLE/PIB (p < 0.001) patients with ≥2 comedications. Among them, the potential effect of DDI was a decrease of DAA serum levels (11% of SOF/VEL and GLE/PIB patients) and an increased concentration of comedication serum levels (14% of SOF/VEL and 42% of GLE/PIB patients). Conclusion: This real-world analysis provided a thorough characterization on the burden of polymedication regimens in HCV patients treated with SOF/VEL or GLE/PIB that expose such patients to an increased risk of DDIs. In our sample population, SOF/ VEL regimen was more frequently detected on elderly patients and on those with ≥2 comedications at risk

Published
2023

7. Analysis of Patients’ Characteristics and Treatment Profile of People Who Use Drugs (PWUDs) with and without a Co-Diagnosis of Viral Hepatitis C: A Real-World Retrospective Italian Analysis

Author

Nava, F, Mangia, A, Riglietta, M, Somaini, L, Foschi, F, Claar, E, Maida, I, Ucciferri, C, Frigerio, F, Hernandez, C, Dovizio, M, Perrone, V, Degli Esposti, L, Puoti, M, Nava F. A., Mangia A., Riglietta M., Somaini L., Foschi F. G., Claar E., Maida I., Ucciferri C., Frigerio F., Hernandez C., Dovizio M., Perrone V., Degli Esposti L., Puoti M., Nava, F, Mangia, A, Riglietta, M, Somaini, L, Foschi, F, Claar, E, Maida, I, Ucciferri, C, Frigerio, F, Hernandez, C, Dovizio, M, Perrone, V, Degli Esposti, L, Puoti, M, Nava F. A., Mangia A., Riglietta M., Somaini L., Foschi F. G., Claar E., Maida I., Ucciferri C., Frigerio F., Hernandez C., Dovizio M., Perrone V., Degli Esposti L., and Puoti M.

Abstract

Purpose: Hepatitis C virus (HCV) spreads from contact with blood of an infected person. HCV infections are common among people who use drugs (PWUDs), when sharing needles, syringes, or other equipment for injected drugs. The advent of pangenotypic direct-antiviral agents (DAA) in 2017 transformed the treatment landscape for HCV, but PWUDs remain a complex and hard-to-treat population with high risk of HCV reinfection. The aim of this real-world analysis was to characterize the demographic and clinical features of PWUDs in Italy, also focusing on comorbidity profile, treatment with DAAs, resource consumptions for the National Health System (NHS). Patients and Methods: During 01/2011–06/2020, administrative databases of Italian healthcare entities, covering 3,900,000 individuals, were browsed to identify PWUDs with or without HCV infection. Among HCV+ patients, a further stratification was made into treated and untreated with DAAs. The date of PWUD or HCV first diagnosis or DAA first prescription was considered as index-date. Patients were then followed-up for one year. Alcohol-dependency was also investigated. Results: Total 3690 PWUDs were included, of whom 1141 (30.9%) PWUD-HCV+ and 2549 (69.1%) PWUD-HCV-. HCV-positive were significantly older (43.6 vs 38.5 years, p < 0.001), had a worse comorbidity profile (Charlson-index: 0.8 vs 0.4, p < 0.001), and high rates of psychiatric, respiratory, dermatological, musculoskeletal diseases and genitourinary (sexually transmitted) infections. Moreover, they received more drug prescriptions (other than DAAs, like anti-acids, antiepileptics, psycholeptics) and had undergone more frequent hospitalization, predominantly for hepatobiliary, respiratory system and mental disorders. DDA-untreated had significantly higher Charlson-index than DAA-treated (0.9 vs 0.6, p = 0.003). Alcoholism was found in 436 (11.8%) cases. Conclusion: This Italian real-world analysis suggests that PWUDs with HCV infection, especially those untreat

Published
2023

21. Cardiovascular autonomic individual profile of relapsing-remitting multiple sclerosis patients and risk of extending cardiac monitoring after first dose fingolimod

Author

Vanoli, E., Montano, N., De Angelis, G., Badilini, F., Mirabella, Massimiliano, Bonavita, S., Patti, F., Bianco, Assunta, Sparaco, M., Chisari, C., Laroni, A., Frigerio, F., Bartezaghi, M., Rossi, S., Turrini, R., Mancardi, G., Mirabella M. (ORCID:0000-0002-7783-114X), Bianco A., Vanoli, E., Montano, N., De Angelis, G., Badilini, F., Mirabella, Massimiliano, Bonavita, S., Patti, F., Bianco, Assunta, Sparaco, M., Chisari, C., Laroni, A., Frigerio, F., Bartezaghi, M., Rossi, S., Turrini, R., Mancardi, G., Mirabella M. (ORCID:0000-0002-7783-114X), and Bianco A.

Abstract

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

Published
2019

23. Diabetes-associated mitochondrial DNA mutation A3243G impairs cellular metabolic pathways necessary for beta cell function

Author

de Andrade, P., Rubi, B., Frigerio, F., van den Ouweland, J., Maassen, J., Maechler, P., de Andrade, P., Rubi, B., Frigerio, F., van den Ouweland, J., Maassen, J., and Maechler, P.

Abstract

Aims/hypothesis: Mitochondrial DNA (mtDNA) mutations cause several diseases, including mitochondrial inherited diabetes and deafness (MIDD), typically associated with the mtDNA A3243G point mutation on tRNALeu gene. The common hypothesis to explain the link between the genotype and the phenotype is that the mutation might impair mitochondrial metabolism expressly required for beta cell functions. However, this assumption has not yet been tested. Methods: We used clonal osteosarcoma cytosolic hybrid cells (namely cybrids) harbouring mitochondria derived from MIDD patients and containing either exclusively wild-type or mutated (A3243G) mtDNA. According to the importance of mitochondrial metabolism in beta cells, we studied the impact of the mutation on key parameters by comparing stimulation of these cybrids by the main insulin secretagogue glucose and the mitochondrial substrate pyruvate. Results: Compared with control mtDNA from the same patient, the A3243G mutation markedly modified metabolic pathways leading to a high glycolytic rate (2.8-fold increase), increased lactate production (2.5-fold), and reduced glucose oxidation (−83%). We also observed impaired NADH responses (−56%), negligible mitochondrial membrane potential, and reduced, only transient ATP generation. Moreover, cybrid cells carrying patient-derived mutant mtDNA exhibited deranged cell calcium handling with increased cytosolic loads (1.4-fold higher), and elevated reactive oxygen species (2.6-fold increase) under glucose deprivation. Conclusions/interpretation: The present study demonstrates that the mtDNA A3243G mutation impairs crucial metabolic events required for proper cell functions, such as coupling of glucose recognition to insulin secretion

Published
2018

26. Theta rhythm alterations – a novel predictive biomarker of epilepsy

Author

Milikovsky, D.Z., primary, Weissberg, I., additional, Kamintsky, L., additional, Lippman, K., additional, Schefenbauer, O., additional, Frigerio, F., additional, Rizzi, M., additional, Sheintuch, L., additional, Zelig, D., additional, Ofer, J., additional, Vezzani, A., additional, and Friedman, A., additional

Published
2017
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27. The Relevance of Early-Warning Systems and Evacuation Plans for Risk Management

Author

Garcia C., Frigerio F., Daehne A., Corsini A., and Sterlacchini S.

Abstract

Early-Warning Systems (EWS) include the provision of timely and effective information, through identified institutions, that allows individuals exposed to hazard to take action in order to avoid or reduce risk and prepare for effective response. EWS are extensive frameworks that integrate different components of risk governance and disaster risk reduction policies with the main purpose of minimizing loss of life and reducing the economic and social impact of a threatening event on the physical assets and populations exposed to hazards. This section describes and analyzes different types of EWS with the aim to connect scientific advances in hazard and risk assessment with management (emergency preparedness and response) strategies and practical demands of stakeholders and end-users. Besides a structural approach, an Integrated People-Centred EWS (IEWS) is also presented. The system is mainly based on prevention as a key element for disaster risk reduction and aims not only to increase the level of awareness and preparedness of the community and decrease its vulnerability, but also to strengthen institutional collaboration, in particular at a local level, in order to assure sustainability of the efforts in the long term and to strength the risk governance process. In this way, the whole disaster cycle can be covered, trying to apply the most advanced technology available and also making the solutions easier to use by people not accustomed to manage these techniques in their daily tasks.

Published
2013

38. P.03.13 COMPARISON OF THE PERFORMANCE OF TWO COMMERCIALLY AVAILABLE TESTS FOR DETERMINATION OF INFLIXIMAB TROUGH LEVELS (IFX-TL) AND ANTIBODIES TO INFLIXIMAB (ATI), PROMONITOR AND IMMUNDIAGNOSTIK, IN INFLAMMATORY BOWEL DISEASE

Author

Daperno, M., primary, Frigerio, F., additional, Guiotto, C., additional, Laura, G., additional, Ercole, E., additional, Lavagna, A., additional, Rigazio, C., additional, Aricò, S., additional, Migliardi, M., additional, Pellerito, R., additional, and Rocca, R., additional

Published
2013
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39. P508 Evaluation of the diagnostic performance of two commercially available tests for infliximab trough levels (IFX-TL) and antibodies to infliximab (ATI) titration in inflammatory bowel disease (IBD)

Author

Daperno, M., primary, Frigerio, F., additional, Guiotto, C., additional, Germano, L., additional, Ercole, E., additional, Aricò, S., additional, Fracchia, M., additional, Rigazio, C., additional, Lavagna, A., additional, Pellerito, R., additional, Migliardi, M., additional, and Rocca, R., additional

Published
2013
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40. Inhibitory activity of IL-1 receptor antagonist depends on the balance between binding capacity for IL-1 receptor type 1 and IL-1 receptor type II

Author

Ruggiero P, Bossù P, Macchia G, Del Grosso E, Sabbatini V, Bertini R, Colagrande A, Bizzarri C, Maurizi G, Di Cioccio V, D'Andrea G, Di Giulio A, Frigerio F, Grifantini R, Guido Grandi, Tagliabue A, and Boraschi D

Subjects
Mice, Inbred C3H, Sialoglycoproteins, Immunology, Receptors, Interleukin-1, Recombinant Proteins, Cell Line, Interleukin 1 Receptor Antagonist Protein, Mice, Mutation, Immunology and Allergy, Animals, Humans, Female, Protein Binding
Abstract

A series of mutants of human IL-1 receptor antagonist (IL-1ra) has been designed by comparison of IL-1ra and IL-1beta structures in order to increase receptor antagonist capacity. Upon in vitro and in vivo assay of IL-1 antagonism, the IL-1ra mutants DoB 0039 (N91-->R), DoB 0040 (T109-->A) and DoB 0041 (N91/T109-->R/A) could inhibit IL-1beta effects more efficiently than wild-type IL-1ra, with DoB 0041 being the most active. Analysis of the receptor-binding capacity of the IL-1ra mutants showed that all three mutants could inhibit binding of IL-1alpha or IL-1beta to IL-1RI-bearing cells more efficiently than wild-type IL-1ra. Conversely, binding of IL-1beta to IL-1RII-bearing cells could be inhibited by DoB 0041 much less efficiently than by wild-type IL-1ra. It is known that the two types of IL-1 receptors (IL-1RI and IL-1RII) play different roles in the regulation of IL-1 activity, with IL-1RI being solely responsible for cell triggering upon IL-1 binding, whereas IL-1RII acts as a scavenger of IL-1 and can thus be considered as a natural IL-1 inhibitor. Thus, the enhanced inhibitory capacity of DoB 0041 as compared with wild-type IL-1ra is explained in terms of better binding to the activating receptor IL-1RI and poorer interaction with the inhibitory receptor IL-1RII.

Published
1997

43. Mapping of receptor binding sites on IL-1 beta by reconstruction of IL-1ra-like domains

Author

Boraschi D, Bossù P, Ruggiero P, Tagliabue A, Bertini R, Macchia G, Gasbarro C, Pellegrini L, Melillo G, Ulisse E, Visconti U, Bizzarri C, Del Grosso E, Andrew Reay Mackay, Frascotti G, Frigerio F, Grifantini R, and Grandi G

Subjects
Mice, Inbred C3H, Binding Sites, Base Sequence, Sialoglycoproteins, Immunology, Molecular Sequence Data, Receptors, Interleukin-1, Peptide Mapping, Interleukin 1 Receptor Antagonist Protein, Mice, Structure-Activity Relationship, Mutagenesis, Site-Directed, Immunology and Allergy, Animals, Humans, Female, Sequence Alignment, Sequence Analysis, Interleukin-1
Abstract

Upon structure comparison between IL-1 beta and its antagonist IL-1ra, single or multiple residues along the IL-1 beta sequence were replaced with the corresponding amino acids present in the IL-1ra protein, in the attempt to identify sites important for receptor binding and for biologic activity on the two molecules. Ten of fifteen mutant proteins had activity comparable to that of wild-type IL-1 beta in three different biologic assays and in receptor binding, indicating that the introduced changes did not influence the functional structure of the protein. Conversely, three mutants (SMIL-9: 127/263 R/T-->W/Y; SMIL-10: 125/127/263/265 T/R/T/Q-->R/W/Y/E; SMIL-15:222/227 I/E-->S/S) showed an increased binding capacity for IL-1RI, not paralleled by increased agonist activity, indicating that the introduced IL-1ra residues could be involved in the nonagonist IL-1RI binding site. On the other hand, two mutants showed diminished binding capacity with concomitant decrease in biologic activity. Both mutants (SMIL-1, five substitutions in the loop 202-214; and SMIL-3, total replacement of the loop 164-173 with the IL-1ra stretch 52-55) included substitutions of residues allegedly important for agonist binding to IL-1RI. Mutant SMIL-3 showed the most profound reduction in binding capacity for IL-1RI (CDw121a) and a more than 1,000-fold reduced biologic activity both in vitro and in vivo, but it retained full capacity of binding to IL-1RII (CDw121b) and acted as a selective antagonist of IL-1RII. From these results the following conclusions can be drawn. IL-1 beta binds to IL-1RI and to IL-1RII through different sites, and the loop 164-173 appears as one of the areas involved in the selective interaction with IL-1RI. Agonist (IL-1 beta) and nonagonist (IL-1ra) binding to IL-1RI occur through distinct sites, with loops 164-173 and 202-214 of IL-1 beta identified as two of the sites selectively involved in agonist binding to the activating receptor.

Published
1995

46. THE EFFECT OF ENGINEERING SURFACE LOOPS ON THE THERMAL-STABILITY OF BACILLUS-SUBTILIS NEUTRAL PROTEASE

Author

HARDY, F, VRIEND, G, VANDERVINNE, B, FRIGERIO, F, GRANDI, G, VENEMA, G, and EIJSINK, VGH

Subjects
EXPRESSION, SURFACE, STEAROTHERMOPHILUS, BINDING LOOP, LIMITED PROTEOLYSIS, GENE, AMINO-ACID, THERMAL STABILITY, RESOLUTION, NUCLEOTIDE-SEQUENCE, THERMOSTABILITY, LOOP, NEUTRAL PROTEASE, BACILLUS, THERMOLYSIN
Abstract

Using genetic techniques the contribution of surface loops to the thermal stability of Bacillus subtilis neutral protease (NP-sub) was studied. Mutations were designed to make the surface of NP-sub more similar to the surface of more thermostable neutral proteases such as thermolysin (TLN). The mutations included the replacement of an irregular loop by a shorter variant and the introduction of a ten-residue beta-hairpin. In general, these drastic mutations had little effect on the production and activity of NP-sub, indicating the feasibility of major structural rearrangements at the surface of proteins. In the most stable mutant, exhibiting an increase in thermal stability of 1.1 degrees C, similar to 10% of the surface of NP-sub was modified. Several NP-sub variants carrying multiple mutations were constructed. Non-additive effects on thermal stability were observed, which were interpreted on the basis of a model for thermal inactivation, that emphasizes the importance of local unfolding processes for thermal stability.

Published
1994

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