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A Computer-Based Methodology to Design Non-Standard Peptides Potentially Able to Prevent HOX-PBX1-Associated Cancer Diseases.

ABSTRACT: In the last decades, HOX proteins have been extensively studied due to their pivotal role in transcriptional events. HOX proteins execute their activity by exploiting a cooperative binding to PBX proteins and DNA. Therefore, an increase or decrease in HOX activity has been associated with both solid and haematological cancer diseases. Thus, inhibiting HOX-PBX interaction represents a potential strategy to prevent these malignancies, as demonstrated by the patented peptide HTL001 that is being studied in clinical trials. In this work, a computational study is described to identify novel potential peptides designed by employing a database of non-natural amino acids. For this purpose, residue scanning of the HOX minimal active sequence was performed to select the mutations to be further processed. According to these results, the peptides were point-mutated and used for Molecular Dynamics (MD) simulations in complex with PBX1 protein and DNA to evaluate complex binding stability. MM-GBSA calculations of the resulting MD trajectories were exploited to guide the selection of the most promising mutations that were exploited to generate twelve combinatorial peptides. Finally, the latter peptides in complex with PBX1 protein and DNA were exploited to run MD simulations and the ΔG_binding average values of the complexes were calculated. Thus, the analysis of the results highlighted eleven combinatorial peptides that will be considered for further assays.

SUBMITTER: Gulotta MR

PROVIDER: S-EPMC8198631 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The rising prevalence of overweight and obesity has a direct correlation with increasing prevalence of hypertension, dyslipidaemia, type 2 diabetes, metabolic syndrome (MetS) and cardiovascular diseases. Most of the previous studies have been cross-sectional in nature and have looked at the prevalence of metabolic syndrome. Despite the clinical and public health importance of this phenomenon, not enough work has been carried out so far to study and remedy this situation. The objectives of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account user sociodemographics, health behaviour, prior disease state and knowledge attitudes and practices.The objective of the proposed study is to develop an innovative user-centred informatics platform that will facilitate delivery of a multifactorial intervention after taking into account users' sociodemographics, health behaviour, prior disease state and knowledge, attitudes and behaviour.A randomised two-group repeated-measures clinical trial design will be used, on 750 subjects from urban, rural and slum areas, in an Indian setting. The study participants will be randomly assigned to either the intervention (computer-based MetS Program, CBMP) or control (printed educational material, PEM) group. Both the groups will undergo screening, learning and evaluation assessments at the time of the visit and at follow-up visits 30, 60 and 90 days after the first visit.The outcomes expected in the intervention group include improvement in Mets-related knowledge, adherence to self-care practices, better quality of life and increased satisfaction with medical care.The study has been approved by the Institutional Review Board of Asian Institute of Public Health (IRB#621). The proposed study will also help us assess the usefulness and challenges of technology to disseminate health education among diverse users. Findings will be disseminated through peer-reviewed publications and national and international conference presentations to various stakeholders and local community health leaders. The ClinicalTrials.gov Identifier is NCT01713465.

Project description:BACKGROUND:Binge-drinking in adolescents is a highly prevalent healthcare problem that associates physical and mental health complications with community implications. This paper describes the design, implementation and evaluation of the first web-based computer tailored intervention aimed at the prevention of binge drinking in Spanish adolescents. METHODS:The Alerta Alcohol program is based on the I-Change Model. First, feedback from focus and Delphi groups are used for cultural adaptation and to obtain further information on the items to be included on the program. A pilot study is then conducted to assess feasibility and to identify strengths and weaknesses. Second, a Cluster Randomized Controlled Trial is conducted to test the effectiveness of Alerta Alcohol in students aged 16 to 18 years. The study is performed in 16 high schools from Andalusia (southern Spain), which are randomized either to the experimental or the control condition (EC and CC). The EC receives the Alerta Alcohol intervention, which consists of four sessions at school (baseline questionnaire, two sessions in three scenarios: at home, celebrations, and public places, and a final evaluation). The adolescents are provided with answers related to their views of each scenario; this information is used to provide highly specific feedback regarding their knowledge, risk perception, self-esteem, attitude, social influence, and self-efficacy. In addition, two booster sessions are given at home to reinforce the previous messages. The CC just completes the baseline and the final evaluation questionnaires and then they are allowed to receive the intervention as well (as a waiting list). Evaluation takes place after four months. The primary endpoint is binge drinking within 30 days prior to the evaluation and alcohol use in the previous week. It is expected that Alerta Alcohol reduce the prevalence of binge drinking by 10%. Follow up analyses are carried out to determine the differences in effectiveness according to the compliance of the program (quality of the implementation). DISCUSSION:The results are expected to be applicable and may incorporate improvements in the practice of the Healthcare and Education Systems. If the program proves to be effective, regional and eventual national implementation should be considered. TRIAL REGISTRATION:Trial registration number (ClinicalTrials.gov): NCT03288896 . This study was retrospectively registered on 19/09/2017.

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A Computer-Based Methodology to Design Non-Standard Peptides Potentially Able to Prevent HOX-PBX1-Associated Cancer Diseases.

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