Browsing by Author "Pereira, Marisa"
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- Modulating protein aggregation in cell models using modified steroidsPublication . Albuquerque, Hélio; Silva, Raquel; Vieira, Sandra; Pereira, Marisa; Soares, Ana Catarina Correia; Santos, Clementina M.M.; Silva, ArturP rotein aggregation is a biological process in which misfolded proteins aggregate and accumulate in intra- or extracellular media. Protein aggregation is intimately linked to the pathogenesis of many neurodegenerative diseases (such as Alzheimer’s, Huntington, Parkinson’s and prion diseases) but also in cancer and cardiovascular pathologies (e.g. atherosclerosis, heart failure and ischemic heart disease).1 However, it is not fully understood how aggregates are formed and how the complex network of chaperones, the proteasome, autophagy and other regulatory factors are involved in their clearance.1 Nevertheless, it is well accepted that lowering protein aggregates back to “normal” levels in cells could be an important therapeutic strategy to control or modulate neurodegenerative diseases.2 In 2015, lanosterol was reported to reverse protein aggregation of crystallin clumps in mouse cataracts, due to its amphiphilic nature, being able to intercalate into and coat hydrophobic areas of large protein aggregates, making these water soluble again.3 Taking into consideration this discovery, we believe that other steroids, such cholesterol (with the appropriate chemical modification),4 can be good lead candidates to lower several types of protein aggregates. In this project a series of new hybrid-steroidal compounds was designed and synthesized, to address protein aggregates in different models and using techniques such as a high-throughput screening (HTS) (Figure 1). The design and synthetic strategy of the compounds, as well as the preliminary disaggregation results in different types of in vitro and ex vivo aggregation models will be discussed and rationalized in terms of structure-activity relationship, whenever possible.
- Steroid–quinoline hybrids for disruption and reversion of protein aggregation processesPublication . Albuquerque, Hélio; Silva, Raquel Nunes da; Pereira, Marisa; Maia, André; Guieu, Samuel; Soares, Ana Raquel; Santos, Clementina M.M.; Vieira, Sandra I.; Silva, ArturReversing protein aggregation within cells may be an important tool to fight protein-misfolding disorders such as Alzheimer’s, Parkinson’s, and cardiovascular diseases. Here we report the design and synthesis of a family of steroid−quinoline hybrid compounds based on the framework combination approach. This set of hybrid compounds effectively inhibited Aβ1−42 self-aggregation in vitro by delaying the exponential growth phase and/or reducing the quantity of fibrils in the steady state. Their disaggregation efficacy was further demonstrated against preaggregated Aβ1−42 peptides in cellular assays upon their endocytosis by neuroblastoma cells, as they reverted both the number and the average area of fibrils back to basal levels. The antiaggregation effect of these hybrids was further tested and demonstrated in a cellular model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new cholesterol−quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the development of new drugs to deal with conformational disorders.