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    • Our biological data also showed that in

    2022-08-04

    Our biological data also showed that, in presence of LEDGF/p75, R or S of glycerol T instead of T4, T8 or T12 loop in the T30695-GQ differently affected the integration activity of the enzyme (Table 2), whereas the position but not the chirality of glycerol T affected the inhibitory efficiency of T30695-GQ variants in the LEDGF/p75 independent assay. According to previous reported model for (HIV-IN)4-T30695 complex [16], the obtained results suggested that all loops of T30695-GQ could be involved in interactions with proteins. Although more in depth studies should be performed to clarify the ability of LEDGF/p75 to affect aptamer-(IN)4 complexes, our results showed that specific modifications at T loops of T30695-GQ could produce suitable tools in studies aimed to clarify the dynamic of allosteric phenomena in HIV-1 IN tetramer complexes during the integration activity. Finally, according to the molecular model proposed by Sgobba et al., that showed T8 loop involved in HIV IN T30695-GQ interaction [16], our T30695-s8 variant consistently exhibited better inhibitory efficiency than T30695 both in presence and in absence of LEDGF/p75. Therefore, the exploration of different S glycerol derivatives at T8 loop should be valuable to improve T30695-GQ biological properties.
    Introduction Since the advent of highly active antiretroviral therapy (HAART) in 1996, the prognosis and life expectancy for those infected with HIV has improved dramatically. Currently, a 20-year-old HIV-positive patient in the U.S. or Canada diagnosed at an early stage of infection and prescribed a current HAART regime is expected to live into their early 70's. Traditionally, HAART regimes comprise two nucleoside reverse transcriptase inhibitors in addition to either a non-nucleoside inhibitor such as efavirenz, or a protease inhibitor.2, 3 However, development of cross-resistance and poor tolerability necessitated the development of new chemotherapeutics targeting alternative components of the viral machinery including the HIV integrase (IN) enzyme. The IN enzyme mediates integration of the viral genome into the CJ-42794 synthesis of the host's T-helper cells, an event representing a point of no return with the host cell becoming a permanent carrier of the viral cDNA.5, 6 Integration occurs across a multi-step sequence which is initiated in the host cell cytosol with 3′processing (3′P) whereby IN cleaves a dinucleotide from each viral DNA terminus at a conserved CA sequence, yielding two reactive 3′ hydroxyl groups.6, 7 Following this processing step, IN associates with a number of viral and cellular proteins, including Lens Epithelium Derived Growth Factor (LEDGF/p75), to form a pre-integration complex (PIC) which subsequently migrates to the nucleus. Within the nucleus, IN catalyses nucleophilic attack of the reactive hydroxyl groups upon the host chromosomal DNA in a process known as strand transfer (ST). In addition to IN having an indispensable role in the life cycle of HIV, there is no known counterpart in mammalian cells which renders the enzyme a highly attractive target for chemotherapeutic development. Initial studies with IN inhibitors focused on the development of compounds capable of coordinating the divalent metal ions within the active site. Predominately, these analogues were constructed around a diketo-acid (DKA) moiety, or a bioisostere thereof, and specifically inhibited the ST reaction (INSTIs). Optimisation of this class culminated in the U.S. Food and Drug Administration (FDA) approved INSTIs raltegravir (RAL), elvitegravir (EVG, Fig. 1, compound 1), and more recently dolutegravir (DTG, Fig. 1 compound 2). To complement this arsenal of INSTIs is an emerging class of allosteric inhibitors often referred to as LEDGINs were developed. These compounds bind within the LEDGF/p75 binding pocket and exhibit a multimodal mechanism of action.8, 9, 10, 11, 12 In addition to impeding LEDGF/p57–IN binding interactions the LEDGINs induce aberrant IN multimerisation, and while only modestly interfering with early steps of HIV replication, they potently disrupt late steps including particle assembly and maturation.8, 9, 10, 11, 12 A member of this class (BI-224436, Fig. 1, compound 3) was progressed to Phase I clinical development. However, this trial was ceased presumably due to enterohepatic recirculation-related PK issues.