Systematic studies of zinc ejection of NCp7 HIV-1 protein by gold(I) complexes.

• Grant number: 13/20334-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2014
• End date: April 28, 2015
• Field of knowledge: Physical Sciences and Mathematics - Chemistry - Inorganic Chemistry
• Principal Investigator: Pedro Paulo Corbi
• Grantee: Camilla Abbehausen
• Host Institution: Instituto de Química (IQ). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The introduction of highly active anti-retroviral therapy (HAART) in the middle of 1990 changed radically the morbidity and mortality rates of the patients infected by the human immunodeficiency virus (HIV). However, HAART is not curative, being a lifelong therapy, causing different side effects and generating drug resistant mutants. Therefore the search for new anti-retroviral drugs is extremely relevant to keep anti-retroviral therapy efficient. Although the HAART improved the life quality of HIV-1 infected patients, the development of a form to eradicate the disease is an important aspect to be considered and investigated. A virus nucleocapsid protein, NCp7, which exerts different functions during virus life cycle and has a mutational non-permissive nature, is a potential target for the rational anti-retroviral drug development. This protein has two zinc fingers (ZF) domains. Most of the investigations of inhibitors of NCp7 are based in electrophilic molecules that cause zinc ejection from the zinc fingers domains, unfolding the protein and inhibiting its function. Numerous metal ions act as zinc ejectors from ZF. Gold(I) compounds, used in the clinic for rheumatoid arthritis as sodium aurothiomalate, aurothioglucose and auranofin presented anti-retroviral activity in vitro. Several phosphinegold(I) compounds inhibited the reverse transcriptase activity in vitro. Auranofin showed to inhibit the viral replication in vivo and also the reservoirs, and the increase in viral loads was not observed after therapy interruption. In our research group was observed that piridinotriphenylphosphineaurate compounds ejected the zinc from ZF domains, keeping the phosphine coordinated for a long time.In this project synthesis of novel gold(I) compounds with a systematic ligand variation are envisaged. The ligands effects on the NCp7 ZF will also be investigated. Aspects as specificity, ejection kinetics, ligand replacement kinetics, non-covalent interactions and cellular uptake will also be considered here.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ABBEHAUSEN, CAMILLA; FERRAZ DE PAIVA, RAPHAEL ENOQUE; BJORNSON, RAGNAR; GOMES, SAULO QUINTANA; DU, ZHIFENG; CORBI, PEDRO PAULO; LIMA, FREDERICO ALVES; FARRELL, NICHOLAS. X-ray Absorption Spectroscopy Combined with Time-Dependent Density Functional Theory Elucidates Differential Substitution Pathways of Au(I) and Au(III) with Zinc Fingers. Inorganic Chemistry, v. 57, n. 1, p. 218-230, JAN 1 2018. (13/20334-0)