Synthesis and in Vitro Screening of New Series of 2,6-Dipeptidyl-anthraquinones: Influence of Side Chain Length on HIV-1 Nucleocapsid Inhibitors

Frecentese, Francesco; Sosic, Alice; Saccone, Irene; Gamba, Enrica; Kristina, Link; Miola, Angelica; Cappellini, Marta; Cattelan, Massimiliano Gianni; Severino, Beatrice; Fiorino, Ferdinando; Magli, Elisa; Corvino, Angela; Perissutti, Elisa; Fabris, Dan; Gatto, Barbara; Caliendo, Giuseppe; Santagada, Vincenzo

doi:10.1021/acs.jmedchem.5b01494

Cited by 15 publications

(55 citation statements)

References 22 publications

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“…Since NC is highly conserved, anti-NC drugs are expected to provide a sustained replication inhibition of the wild type and HIV-1 drug-resistant strains. Three classes of NC inhibitors have been reported based on the mechanism of action: (i) zinc ejectors, , (ii) noncovalent NCIs binding to nucleic acid partners of NC, , and (iii) noncovalent NCIs binding to NC. , The development of NCIs directly binding to NC is currently our main research area, as it is expected to overcome the selectivity and toxicity issues intrinsically related to NCIs belonging to the classes (i and ii). In this work, we describe the most recent advances achieved, leading to the identification of a new class of NCIs showing both good antiviral activity as well as promising in vitro and in vivo profiles.…”

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confidence: 99%

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

Malancona

Mori

Fezzardi

et al. 2020

ACS Med. Chem. Lett.

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The HIV-1 nucleocapsid (NC) protein is a small basic DNA and RNA binding protein that is absolutely necessary for viral replication and thus represents a target of great interest to develop new anti-HIV agents. Moreover, the highly conserved sequence offers the opportunity to escape the drug resistance (DR) that emerged following the highly active antiretroviral therapy (HAART) treatment. On the basis of our previous research, nordihydroguaiaretic acid 1 acts as a NC inhibitor showing moderate antiviral activity and suboptimal drug-like properties due to the presence of the catechol moieties. A bioisosteric catechol replacement approach led us to identify the 5-dihydroxypyrimidine-6-carboxamide substructure as a privileged scaffold of a new class of HIV-1 NC inhibitors. Hit validation efforts led to the identification of optimized analogs, as represented by compound 28, showing improved NC inhibition and antiviral activity as well as good ADME and PK properties.

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confidence: 99%

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

Malancona

Mori

Fezzardi

et al. 2020

ACS Med. Chem. Lett.

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“…Gatto and colleagues reported a series of anthraquinones symmetrically substituted with aminoacidic side-chains containing terminal amino groups (compounds 29-31 Fig. 4) [54][55][56]. The aromatic scaffold is meant to stack with nucleobases whereas the cationic side-chain can serve to stabilize the interaction via salt bridges with the phosphodiester backbone.…”

Section: Anthraquinonesmentioning

confidence: 99%

NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders

Iraci

Tabarrini

Santi

et al. 2018

Drug Discovery Today

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Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity. Although covalent NCp7 inhibitors have already been detailed in the first part of this review series, the focus here is based on noncovalent and NA-binder inhibitors and on the analysis of the NCp7 3D structure to deliver fruitful insights for future drug design strategies.

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“…Compared to available NC inhibitors, CN14_17 has a novel mechanism of action as it fully prevents the annealing of complementary NA sequences. Moreover, with respect to available NC inhibitors targeting NAs such as for instance functionalized anthraquinones, − CN14_17 shows a clear preference for single-stranded sequences rather than NA duplexes, thus becoming a privileged agent for binding to NA sequences specifically targeted by the NC within the HIV-1 replication cycle, possibly with limited off-target effects. From a medicinal chemistry standpoint, CN14_17 structure offers multiple opportunities for chemical modification, thus becoming a preferred candidate for further hit-to-lead optimization studies specifically aimed at improving the therapeutic index.…”

Section: Discussionmentioning

confidence: 99%

A Class of Potent Inhibitors of the HIV-1 Nucleocapsid Protein Based on Aminopyrrolic Scaffolds

Ciaco

Humbert

Réal

et al. 2020

ACS Med. Chem. Lett.

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The HIV-1 nucleocapsid protein 7 (NC) is a potential target for effective antiretroviral therapy due to its central role in virus replication, mainly linked to nucleic acid (NA) chaperone activity, and low susceptibility to drug resistance. By screening a compounds library, we identified the aminopyrrolic compound CN14_17, a known carbohydrate binding agent, that inhibits the NC chaperone activity in the low micromolar range. Different from most of available NC inhibitors, CN14_17 fully prevents the NC-induced annealing of complementary NA sequences. Using fluorescence assays and isothermal titration calorimetry, we found that CN14_17 competes with NC for the binding to NAs, preferentially targeting single-stranded sequences. Molecular dynamics simulations confirmed that binding to cTAR occurs preferably within the guanosine-rich single stranded sequence. Finally, CN14_17 exhibited antiretroviral activity in the low micromolar range, although with a moderate therapeutic index. Overall, CN14_17 might be the progenitor of a new promising class of NC inhibitors.

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Synthesis and in Vitro Screening of New Series of 2,6-Dipeptidyl-anthraquinones: Influence of Side Chain Length on HIV-1 Nucleocapsid Inhibitors

Cited by 15 publications

References 22 publications

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

5,6-Dihydroxypyrimidine Scaffold to Target HIV-1 Nucleocapsid Protein

NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders

A Class of Potent Inhibitors of the HIV-1 Nucleocapsid Protein Based on Aminopyrrolic Scaffolds

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