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This HPC project corresponds to the second part of the computational working package of the project 2022.05718.PTDC, already approved by FCT (“Exploiting monoterpene indole alkaloid derivatives for overcoming resistance in BRCA-deficient cancers. In silico characterization of binding modes”).
The group of Prof. Maria J.U Ferreira (Co-PI; imed/FFUL) identified a monoterpene indole alkaloid derivative (BBIT20) with the ability to target homologous recombination DNA repair defects by disrupting the BRCA1-BARD1 heterodimer in triple-negative breast and ovarian cancer cells. The BRCA1 and BARD1 proteins, both involved in homologous recombination, have been associated with altered DNA repair mechanisms in several different types of cancer, such as pancreatic tumors, advanced ovarian and triple-negative breast cancer. BBIT20 showed promising in vitro and in vivo antitumor activity while in synergistic interaction with PARP inhibitor Olaparib and cisplatin. BBIT20 is patented and is the first reported disrupter of the BRCA1-BARD1 complex and may be a strong starting point for the continued development of new anticancer agents against the harder to treat cancers with very few effective therapeutic options.
The goals of this project are to find the BBIT20’s binding mode and thereafter allow the guided development of new effective plant-derived alkaloids capable of reversing drug resistance in cancer cells, through disruption of the BRCA1-BARD1 complex. BBIT20’s binding mode will be characterized through computational approaches. The binding hot spots were already identified by molecular docking in the first part of the running FCT project. Now, in this HPC project, molecular dynamics will help understand the type of interaction and mode of action. A rational for the molecular derivatization of compounds for the phytochemical studies will be established, that will help to clarify structure-activity trends and the design of novel analogs with improved binding capability.
Past
2025-05-28
2024-05-29
FCT
No Acronym
A computationally assisted drug development pipeline for challenging cancers with very few effective therapeutic options
The main aim of this project is to develop a nanotechnological-based product for insulin delivery, for improvement of wound healing and treatment of wound-related problems, improving the patients quality of life.
Past
2021-08-01
2018-08-01
FCT
NANO WOUND
A nanotechnological approach for topical administration of insulin for wound healing
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The Nipharmin aim is to increase the potency of Nipharmins and to develop Nipharmin-based antibacterial technologies. In this context, the synthesis of new derivatives and further studies for understanding their mechanism of action are necessary. We formed a multidisciplinary team to develop this new family of antibacterials and to investigate their potential in biotechnological applications.
Past
2019-12-31
2018-01-01
Nipharmin
a new antibacterial scaffold and biological applications
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This project focused on the development of novel abietane cationic amphiphiles (ACAs) by chemical modification of dehydroabietic acid (DHA), leading to cationic amide derivatives by condensation of the DHA carboxyl function with the amine group of biogenic polyamines (spermine) and basic proteinogenic amino acids (arginine). The presented project performed a screening of antimicrobial activities of the compounds DHA and ACA hemi synthesis intermediary (ACA-Int) against a collection of Gram-positive, Gram-negative bacteria and yeasts; toxicological studies to assess if the compounds had antimicrobial and not citotoxic properties; and microencapsulation and stability studies to evaluate the chemical behavior and stability of the tested compounds.
Past
2021-01-01
2020-01-01
ACA
Abietane Cationic Amphiphiles (ACA) to tackle resistant bacteria
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The goal of ACFs project is to develop new metal-organic frameworks (MOFs) of antibiotics to increase their solubility, and consequently bioavailability, trying also to explore synergetic effects with the metal, such as zinc, silver and bismuth, to increase the antibiotic’s efficacy. Actually, both factors lead to enhanced efficacy. MOFs proposed herein are also a viable way for a more controlled delivery and release of antibiotics.
Another important point of ACFs project is that mechanochemistry is the main synthetic pathway proposed in this project. This is an environment-friendly technique that drastically reduces the amount of solvents and it has proven to be very efficient in different areas including MOFs’ synthesis.
The interest on metal-organic frameworks towards pharmacological applications has been increasing, especially for controlled drug delivery and release. However, the coordination of metals can also be an alternative way to induce significant changes in previously known drugs, changing important properties such as solubility and bioavailability, with the further advantage that synergetic effects of the metal can be explored enhancing its performance.
Bactericidal agents, including antibiotics, drastically reduced the number of deaths caused by infections over the last 70 years. However, due to their misuse and abuse, many microorganisms developed resistance mechanisms, causing only in Europe approximately 25000 deaths/year, an economic burden over 1.5 bilion € and productivity losses. Thus, there is a growing concern about the proliferation of these multi-resistant Gram-negative microorganisms against which the antibiotics have become less effective and it is indeed one of the great challenges of today’s society.
Past
2022-06-29
2018-06-30
FCT
ACFs
Antibiotic Coordination Frameworks as a Way to Enhance the Bioactivity of the Drugs
Skin cancer is the most diagnosed type of cancer in the world, with excessive exposure to ultraviolet (UV) radiation from the Sun being its main cause. Oxidative stress, one of the factors responsible for the development of carcinomas, is also associated with frequent exposure to UV radiation. The use of photoprotective formulations is the most effective measure to protect against the malignant effects of this type of radiation. In addition to containing elements that absorb and/or reflect them, they also contain components that can help with skin homeostasis, such as antioxidant agents. In this study, ferulic acid, a natural compound recognized as a potential antioxidant, was used, together with two solar filters, bemotrizinol and octyl triazone, to carry out biosafety and efficacy methods, with the aim of improving techniques, in addition to a better elucidation of the effects of ferulic acid. In vivo, in vitro and ex vivo techniques were used to characterize elements such as inflammatory potential, antioxidative potential, molecule permeability and hydration.
Past
2018-10-10
2018-09-15
No Acronym
Antilipoperoxidative and anti-inflammatory effects of multifunctional sunscreens containing ferulic acid
It is crucial for the Pharmaceutical and Cosmetic Industries to improve the efficacy of drug delivery systems. Nonetheless, there are several challenges to overcome in this process, such as poor drug solubility, loading or release and even the low stability of these systems, while ensuring the safety of the developed formulations. Ionic liquids may be a valuable strategy to surpass these challenges since through synthesis they may be tailored to attain the most suitable properties for the required applicability and also because they may be incorporated into various types of solutions, thus facilitating their incorporation into different formulations. Thus, in this study, several ILs will be synthesized and their applicability as functional excipients, at non-toxic concentrations, will be evaluated in different delivery systems.
Past
2021-06-30
2020-01-01
No Acronym
Applicability of Tailored Ionic Liquids in Drug Delivery Systems
The predominant hypothesis for Alzheimer's disease (AD) is amyloid, which establishes changes in the proteolytic processing of amyloid precursor protein resulting in the accumulation of amyloid beta peptide (Aβ), forming amyloid plaques, which trigger an immunological response that promotes neuroinflammation and neurodegeneration. However, the association between genetic and non-genetic risk factors for the development of neuroinflammatory diseases, mainly AD, has been widely discussed in the scientific community and much is said about the influence of the intestinal microbiota in modulating neuro-immune functions. and strong evidence reinforcing the gut-brain link has emerged in recent decades.
Therefore, endotoxins, especially lipopolysaccharide (LPS), have been adopted as a strong non-genetic risk factor for AD neurodegeneration as they promote activation of both systemic and central pro-inflammatory pathways, in addition to having already been documented. presence of LPS in Aβ peptides in amyloid plaques and vascular endothelium of patients with AD. Based on the above, this research proposal aims to elucidate through which neuro-immune or systemic mechanisms an inflammatory bowel disease can influence cognitive decline and a neuroinflammatory process.
Ongoing
Unknown
Unknown
No Acronym
Assessment of the peripheral immune response profile in the neurodegeneration process due to intestinal inflammation PI Sérgio Andrade
Atopic dermatitis (AD) is the biggest threat among skin conditions in terms of causing patients’ disability and its prevalence is still rising every day [1, 2]. A hallmark of AD is the epidermal barrier dysfunction due to abnormal lipid metabolism causing alterations in the ceramides and fatty acid profiles [3, 4]. Gold standard approaches to treat AD include the daily administration of topical emollients together with the reactive administration of glucocorticoids (GC) during the crisis [5]. This therapeutic approach is far from ideal due to corticophobia and the safety issues of GC therapy. In this context, the proactive regimen is gaining more and more followers, comprising the long-term and low-dose administration of GC and emollients in pre-lesional areas [5, 6]. Sustainable technological approaches are hot topics in R&D&I and in current European Union and UnitedNations development policies. Europe needs locally produced biomaterials as the basis for innovative formulations, among which Hermetia illucens larvae oil seems to be particularly promising to tackle AD due to its fatty acid composition [7, 8]. Moreover, biobased ionic liquids are recognized as green functional materials with great potential to be applied in drug delivery systems [9-12]. Lipid-based nanocarriers seem to be the most suitable platform, due to skin compatibility [13], to combine these biomaterials with barrier enhancing ceramides in order to ultimately deliver emollients and low-dose GC in a cutting-edge formulation to tackle AD.
THE STRATEGY FOR INNOVATION
BIOMATNANO4AD aims to fulfil the current needs in AD management through a bioinspired, nanotechnological, and sustainable approach combining multifunctional biomaterials in lipid-based nanocarriers that cansynergically perform as GC delivery systems and topical emollients. The pentagonal coalition of ceramides, insect oil, ionic liquids, nanotechnology, and glucocorticoids in an innovative multifunctional nanoformulation will allow overcoming existing therapeutic limitations of AD. The product development strategy will be based on the initial optimization and characterization of lipid-based nanocarriers, followed by enhancement of nanosystem performance using biobased ionic liquids. The optimized nanosystems by quality-by-design(QbD) strategies will then proceed to in vitro and in vivo safety assessments. Finally, the efficacy of biocompatible nanoformulations will be tested through in vitro and in vivo methodologies. At the end of BIOMATNANO4AD, it is expected that at least one nanoformulation will have reached a preclinical stage, with potential to make a significant contribution towards a cost-effective treatment to ultimately upgrade the quality of life for AD patients.
THE RIGHT KNOW-HOW
The accomplishment of the ambitious objectives ofBIOMATNANO4AD will be ensured by the know-how of a multidisciplinary team of CBIOS researchers and by the strategic collaborations with a biotech company (EntoGreen) andleading scientific institutions (LAQV and Vienna University). Expertise in the optimization of nanoformulations following a QbD approach [14] decreases the risk and increases the capacity to obtain a nanosystem with optimal stability characteristics, and an adequate safety and efficacy performance. Proficiency in taking full advantage of bioinspired products will be useful in the application of ceramides, insect oil, and ionic liquids in skin formulations [7-12]. Finally, the advanced skills of the research team also enable the successful invitro and in vivo assessment of the cytotoxicity and bioactivity performances of the innovative formulations [11, 15-17]. Meticulously planned collaborations with partners of excellence have been established to further boost product development. This befitting team will also be dedicated to dissemination and communication activities so that the major breakthroughs of BIOMATNANO4AD can be shortly available for the scientific community, academia, pharmaceutical industry, patients’ associations, and general society.
Past
2023-10-30
2021-11-01
FCT
BIOMATNANO4AD
Bioinspired materials in nanosolutions to tackle atopic dermatitis
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The Erasmus Mundus Design Measures project in Natural products chemistry for Bioactives Application (BioNatural) will be a 2-year international program built up by 4 Universities, and 4 European countries: Lusófona University - COFAC (ULusófona, PT); Università degli Studi di Siena (UNISI, IT); Universitat Ramon Llull (RLU, ES); and, Namur University (NU, BE). BioNatural will be entirely taught in English and it will lead to a multiple master’s degree diploma. Natural products are important sustainable sources of bioactive compounds with high potential to be used in several applications, including, pharmaceutics, dermocosmetics, medical devices, food supplements, and smart materials.
