Research lines

p53

Responsible Investigator: Maria M. M. Santos

The tumor suppressor protein p53 is inactivated in all types of human cancers, either by negative regulation, by mutation or deletion of its gene. Specifically, in tumors that retain wild-type (wt) p53 status, p53 is inactivated by interaction with negative regulators, such as MDM2 and MDMX. These two proteins are found to be overexpressed in several different types of cancers, and the restoration of p53 activity by inhibition of these proteins is now considered an important approach for cancer treatment. This research line is focused in the discovery of highly potent and selective small-molecules acting as dual p53-MDMs protein-protein interaction inhibitors, as well as reactivators of mutant p53.

Quadruplex Nucleic Acids Targeting

Responsible Investigator: Alexandra Paulo

The four-stranded structures formed by the guanine-rich sequences of nucleic acids (DNA or RNA), termed G-quaduplexes (G4), are emerging as important nanostructures in the field of medicine. Their presence in human genome/transcriptome and in the genome of human pathogens, as well as their involvement in the regulation of several cellular processes turn these nucleic acid structures into promising drug targets. This line of research is focused on the discovery of novel and more selective anticancer and anti-infectious drugs by designing and synthesising small molecules that target G4 structures in oncogene promoter regions of human cancer cells and/or in genome of viruses, malaria parasite and M. tuberculosis.

Prodrug development, stability and metabolic studies

Responsible Investigator: Ana Paula Francisco

Prodrug approach is a proved useful tool to optimize both physicochemical and pharmacological properties of drugs and decrease toxicity. In the past 10 years 12% of all approved small-molecules by FDA were prodrugs. This research line is focused in the design and development of new prodrugs as a tool for chemical optimization of bioactive molecules with relevant properties in anticancer therapy. Chemical and metabolic studies are also an important part of this research line.

Tuberculosis

Responsible Investigator: Luís Constantino

Alternatives to effectively treat this disease are urgently needed and eradication of tuberculosis is included in target goals of the United Nation by 2030. In our group we have been developing with success ester prodrugs of pyrazinoic acid that addressed efficiently pyrazinamide resistance in M. tuberculosis and demonstrated activities higher than the reference molecule. This line of research directed us to new alternatives to treat tuberculosis namely prodrugs of weak acids with long chain alcohols and more recently nitro containing benzamides and esters acting as covalent dprE1 inhibitors.

Projects