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  • br Introduction Currently HIV infection treatment guidelines

    2021-09-17


    Introduction Currently, HIV-1 infection treatment guidelines adopted in USA and EU provide for the simultaneous administration of three antiretroviral drugs (HAART “Highly Active Anti-Retroviral Therapy”) in severely compromised patients [[1], [2], [3]]. Coupling at least two different mechanisms of action, (i.e. nucleoside reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor) this therapeutic approach interferes at different stages of the viral life 597 and efficiently suppresses the viral replication, both reducing the risks of disease-related morbidities and increasing the life expectancy. Nevertheless, significant side effects associated with poor drug tolerability compromises the long-term treatments with HAART [4]. Indeed, recent data show that an increasing number of patients stop HAART mainly for the persistence of severe side effects [2]. These behaviors in turn trigger the evolution of drug resistant viral phenotypes which pose the major clinical problem. Among the potential anti-HIV drugs, some G-quadruplex (GQ) forming aptamers have initially shown particularly promising properties [5]. As an example, the 17-base oligonucleotide (ON) named T30177 (GGTGTGGGTGGGTGGGT, Fig. 1a) inhibits HIV-1 integrase at nanomolar concentrations [6]. Phase I clinical trials of Zintevir, an analog of T30177 containing phosphorotioate groups at 597 specific positions, demonstrated its potent antiviral activity on humans; however, without significant reasons, Phase II was discontinued. Additional studies showed that the T30177 variant, named T30695 (GGGTGGGTGGGTGGGT, Fig. 1b) in which the depletion of the T residue at position 3 produces a continuous 5′-end G3 tract, had increased antiretroviral activity with respect to the parent variant [7,8]. Similarly to T30177, T30695 also binds to HIV-Integrase, inhibiting the enzymatic activity at 3′-end processing stage. A sub-sequent revaluation of pharmacological properties of T30177 and its variants also showed that they bind to the viral envelop protein gp120, impairing the host-viral CD4-gp120 interaction [9]. However, a delivery system able to vehicle anti-HIV-1 IN aptamers into infected cell nucleus was successfully developed, thus increasing the pharmacological potentiality of these molecules as HIV-1 IN inhibitors [10,11]. Structure-activity studies established a tight correlation between the GQ stabilities and the integrase inhibitory efficiencies of these aptamers. [7,8] Recently, Phan and coworkers have solved both the T30177 and T30695 GQ structures in buffered solution using NMR techniques [12,13] (Fig. 1, a and b). Elegantly overcoming the difficulties related to the symmetry of these GQ typologies, they have shown that parallel-stranded monomers of both T30177 and T30695-GQs stack at 5′-ends to form very stable GQ dimers. However, dissecting the exact binding mode of T30695 to IN has remained elusive due to the biological complexity of the viral integration machinery, which includes the ability of IN to adopt various multimeric forms [14,15]. Sgobba et al. built a molecular model for (HIV-IN)4-93del complex [16] and suggested that T30695 could interact with HIV-1 IN in a similar manner. Indeed, 93-del is a 16-mer ON (GGGGTGGGAGGAGGGT), firstly reported as an inhibitor of the RNAse H activity, that also exerts HIV-IN inhibition at nanomolar concentration [17,18]. It adopts a dimeric GQ structure, (Fig. 1c) named interlocked, comprising two parallel-stranded GQ subunits, which are singularly engaged with each other through the G-base at the 5′-end [17]. In the proposed (HIV-IN)4-aptamer complex models, T30695 or 93-del GQ occupies the positively charged cavity of HIV-1 IN tetramer. The aptamers bind to an IN tetramer, principally, through their phosphate groups, interacting with basic residues and amide backbones mainly localized at the base of the IN tetramer cavity. Further interactions could involve T bases in the loops of the GQs. Because of their six and two single T loops, T30695 and 93-del GQs could exhibit different binding energy interactions with HIV-1 IN tetramer, with more favorable free energy variation values obtained for the formation of (HIV-IN)4-T30695 complex [16].