P
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.Thanks are due to University of Aveiro, FCT/MEC, Centro 2020 and Portugal2020, the COMPETE program,
and the European Union (FEDER program) via the financial support to the QOPNA research project (FCT UID/QUI/00062/2019), to
the IBiMed Research Unit (UID/BIM/04501/2013), to the Portuguese NMR Network, and to the PAGE project “Protein aggregation
across the lifespan” (CENTRO-01-0145-FRDER-000003), including H. M. T. Albuquerque Post-Doctoral grant (BPD/UI98/4861/2017)
and R. Nunes da Silva Post-Doctoral grant (BPD/UI98/6327/2018).info:eu-repo/semantics/publishedVersio
