Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

Sun, Songkai; Huang, Boshi; Li, Zhuo; Wang, Zhao; Sun, Lin; Gao, Ping; Kang, Dongwei; Chen, Chin Ho; Lee, Kuo‐Hsiung; Daelemans, Dirk; Clercq, Erik De; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong

doi:10.1016/j.bmcl.2020.127287

Cited by 3 publications

(2 citation statements)

References 22 publications

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“…One possible alternative to the administration of multiple drugs would be the administration of a single drug with multiple targets. It has been shown that dual-target compounds exhibit superior antiviral activity compared to single-target drugs. , In this line of antiviral drug development, we have designed and synthesized an NDI–tetraazacycloalkane conjugate ( 5 ), which tethers an NDI moiety that binds to HIV-1 LTR G4s, to the [13]aneN4 moiety that mimics AMD3100 , a cyclam-containing macrocyclic antiviral drug that blocks HIV entry into cells by binding the CXCR4 alpha-chemokine coreceptor . The conjugation of the cyclam analogue to NDI has been synthetically obtained to retain its ability to stabilize the most relevant G4 structures (LTR-III and LTR-IV) present in the HIV-1 LTR promoter.…”

Section: Discussionmentioning

confidence: 99%

Naphthalene Diimide–Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

Nadai,

Doria,

Frasson

et al. 2024

ACS Infect. Dis.

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Human immunodeficiency virus 1 (HIV-1) therapeutic regimens consist of three or more drugs targeting different steps of the viral life cycle to limit the emergence of viral resistance. In line with the multitargeting strategy, here we conjugated a naphthalene diimide (NDI) moiety with a tetraazacycloalkane to obtain novel naphthalene diimide (NDI)−tetraazacycloalkane conjugates. The NDI inhibits the HIV-1 promoter activity by binding to LTR G-quadruplexes, and the tetraazacycloalkane mimics AMD3100, which blocks HIV entry into cells by interfering with the CXCR4 coreceptor. We synthesized, purified, and tested the metal-free NDI−tetraazacycloalkane conjugate and the two derived metal−organic complexes (MOCs) that incorporate Cu 2+ and Zn 2+ . The NDI-MOCs showed enhanced binding to LTR G4s as assessed by FRET and CD assays in vitro. They also showed enhanced activity in cells where they dose-dependently reduced LTR promoter activity and inhibited viral entry only of the HIV-1 strain that exploited the CXCR4 coreceptor. The time of addition assay confirmed the dual targeting at the different HIV-1 steps. Our results indicate that the NDI-MOC conjugates can simultaneously inhibit viral entry, by targeting the CXCR4 coreceptor, and LTR promoter activity, by stabilizing the LTR G-quadruplexes. The approach of combining multiple targets in a single compound may streamline treatment regimens and improve the overall patient outcomes.

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Section: Discussionmentioning

confidence: 99%

Naphthalene Diimide–Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

Nadai,

Doria,

Frasson

et al. 2024

ACS Infect. Dis.

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“…Within the HIV virus life cycle, NCp7 plays a role in reverse transcription, integration, autocatalysis of Gag-Pol, and promotion of Gag assembly. − NCp7 has been investigated as a target for small molecules against HIV for a long time, − and both covalent and noncovalent inhibitors have been reported with antiviral activities in the low micromolar range. − While NCp7 inhibitors are less potent compared with other classes of anti-HIV drugs, the highly conserved sequence of NCp7 in HIV makes this an attractive target for the development of antiviral drugs that would be less susceptible to viral resistance.…”

mentioning

confidence: 99%

Prodrug Strategy Extends the Use of Anti-HIV Sulfanylbenzamides for Application In Vivo

Robello,

Nikolayevskiy,

Scerba

et al. 2023

ACS Pharmacol. Transl. Sci.

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Sulfanylbenzamide thioesters are molecules with anti-HIV activity that disrupt zinc coordination in the viral protein NCp7. These molecules are useful as topical microbicides; however, they are too unstable to be used systemically. In this article, a nitroimidazole prodrug was used to protect the sulfanylbenzamide to convey blood stability and oral bioavailability to the molecule. Studies on the molecule called nipamovir were performed to assess the rate of prodrug cleavage, antiviral activity, mechanism of metabolism, and in vivo pharmacokinetics in several different species. An efficient and inexpensive synthesis of nipamovir is also described. The results indicate that nipamovir could be further developed as a new type of drug to treat HIV infection.

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Advances in drug structure-activity-relationships for the development of selenium-based compounds against HIV

Shi,

Xu,

Ding

et al. 2023

Expert Opinion on Drug Discovery

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Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

Cited by 3 publications

References 22 publications

Naphthalene Diimide–Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

Naphthalene Diimide–Tetraazacycloalkane Conjugates Are G-Quadruplex-Based HIV-1 Inhibitors with a Dual Mode of Action

Prodrug Strategy Extends the Use of Anti-HIV Sulfanylbenzamides for Application In Vivo

Advances in drug structure-activity-relationships for the development of selenium-based compounds against HIV

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