Acronimo: STRAND

Titolo: Tackle HIV-1. Silencing viral LTR promoter by Target-tailored G-quAdruplex ligaNDs.

Codice Progetto: 2022BL3L7A

Responsabile scientifico per il DMM: Prof.ssa Ilaria FRASSON
Coordinatore: Università degli Studi di PAVIA - Prof. Filippo DORIA

Partner-Unità di ricerca: Università degli Studi "Magna Graecia" di CATANZARO - Università degli Studi di PADOVA

Bando: PRIN 2022 - Decreto Direttoriale n. 104 del 02-02-2022
Durata: 28/09/2023 - 27/09/2025 (24 mesi)

Finanziamento progetto: € 205.357,00 - CUP C53D23004410001

 

Abstract del progetto

HIV is the deadliest pandemic of our time, affecting 79 million people worldwide among which 1.5 million people infected in 20201. It establishes a persistent infection in human hosts, with the depletion of CD4 + lymphocytes, which results in defective cellular immunity leading to full-blown AIDS. Although significant progress has been made in improving the life expectancy of HIV-positive patients, there is currently no strategy to prevent, cure or even eradicate the infection. As a result, HIV-1 infections and the resulting disease progress are expected to remain a major cause of death worldwide with a high impact on health costs. HIV-1 is characterized by a single-stranded RNA (ssRNA) genome that, once retrotranscribed into DNA by the viral reverse transcriptase enzyme, integrates into the host chromosome giving rise to a life-long infection. In the long terminal repeat (LTR) promoter of the integrated HIV-1 genome, three overlapping G-quadruplexes (G4s) exist, namely LTR-II –III and –IV. G4s are non-canonical supramolecular structures that are recognized as key regulator elements in biological processes. Specifically, we demonstrated that the stabilization of LTRIII G4 folding lead hampered viral transcription2,4. Thus, the possibility of selectively stabilizing its G4 conformation by small molecules is highly intriguing, as it foresees stable viral silencing. Despite the large variety of G4 ligands (G4L), a compound displaying a clear-cut selectivity has not been proposed yet. In this context, the peculiar quadruplex-duplex junction of the LTRIII G4 represents the most promising structural motif for the design of novel effective and selective ligands5. Indeed, the engineering of G4L capable of binding simultaneously to both the G4 structure and the duplex portion of LTRIII G4 represents a solid strategy for obtaining high binding selectivity. Thus, the main goal of this project is to develop selective compounds targeting LTRIII G4 to i) offer new anti-HIV-1 compounds, with a novel and unique target, to be used in combination with current drugs (to prevent or treat resistant viral strains); ii) provide selective binders with the unique property of irreversible proviral genome alkylation, with the possibility of curing the infection. To reach this goal, a stepwise approach divided into two WP will be employed. WP1 aims to increase the selectivity: the compounds that best bind LTRIII's guanine tetrad will be conjugated to those that best intercalate its stem-loop. WP2 aims to stabilize the G4-binding: conjugation of hit-compounds from WP1 to an alkylating triggerable subunit, that alkylates the target only once the drug has recognized it, upon external stimulation. Each step will provide compounds with innovative features that will be tested directly as antiviral molecules.