Screening and developing of a novel family of natural and synthetic HIV Integrase inhibitors which do not interfere with V(D)J recombination


Acronyme: INinRAGI
Call: HIVERA JTC2014
Implementation period: 01.09.2015. – 31.08.2018.
Project coordinator: Clinical Hospital Colentina, Romania
Project partners:

University of Szeged, Hungary
Institute of Biochemistry of The Romanian Academy, Romania
Latvian Institute of Organic Synthesis, Latvia
National Center for Epidemiology, Hungary

Leader of Latvian team: Dr. chem. Edgars Ābele
Total costs: 560 000 EUR
Costs for Latvian partner: 150 000EUR

After birth newborn infants from HIV infected mothers have to be subjected to prophylactic treatment to prevent viral infection. HIV Integrase(IN) is the enzyme that mediates the viral genome integration into the host cells chromosomes and its catalytic prevention represents a major way to stop the viral infection. Despite its major clinical advantages the treatment with IN inhibitors(INi) in newborns induces a paradoxical situation. Because HIV-IN resembles in its structure and reaction mechanism to RAG1 protein, which assembles the lymphocytes antigen receptors, INi medication interferes with the ability of treated patients to develop a normal immune response. INinRAGI project is targeted to solve the major drawback of INi treatment that it cannot be addressed to newborns exposed to high risk acquiring HIV-1 infections. The major goal of project is to test new HIV specific Integrase inhibitory compounds which do not interfere with RAG somatic recombination. Project proposes to develop rapid, low cost, efficient FRET screening assays. With them will be HTP screen first a library of natural compounds (NP) of herbal origin. Informed by the best selected NPs we will in silico design and synthesize a derivatized set of HIV-INi compounds which will be again screened in vitro for dual HIV Integrase inhibition and RAG noninterference effects. The uniquely discovered lead compounds will also be tested in immune B cell progression assays and for their antiretroviral potency on HIV infected T cells.