Advances in rationally designed dual inhibitors of HIV-1 reverse transcriptase and integrase

Gu, Shuang‐Xi; Xue, Ping; Ju, Xin; Zhu, Yuan‐Yuan

doi:10.1016/j.bmc.2016.09.025

Cited by 34 publications

(15 citation statements)

References 54 publications

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“…Mechanism research revealed that two compounds target two key viral enzymes, HIV-1 RT and IN, indicating that K-41A and K-41Am are actually multi-target compounds against HIV-1, which is in line with the current developmental trend of anti-HIV drug discovery. It is believed that multi-target anti-HIV drugs have a better therapeutic effect and less drug resistance than single-target drugs [15].…”

Section: Discussionmentioning

confidence: 99%

“…PR plays an important role in the mature of the virus [14]. Because the human host does not have the similar proteins as these viral enzymes, HIV-1 RT, IN, and PR are crucial targets in study of new anti-HIV drugs due to their importance and uniqueness in viral replication [15]. Antiretroviral drugs acting on different viral targets have proved successful in HAART [16].…”

Section: Introductionmentioning

confidence: 99%

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Polyether antibiotics K-41A and K-41Am inhibit HIV-1 replication via suppressing the activities of HIV-1 reverse transcriptase and integrase

et al. 2020

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Introduction: K-41A is a known compound with antibacterial activity against gram-positive bacteria and coccidia. In our screening of anti-HIV compounds, we found polyether antibiotic K-41A and its analogue K-41Am isolated from a marine-derived Streptomyces sp. SCSIO 01680 exhibited anti-HIV activity. Material and methods: In this study, we characterised the anti-HIV activity of K-41A and K-41Am as well as the mechanism(s) involved. The dose-dependent inhibitory effects of K-41A and K-41Am on HIV-1 replication were observed in the TZM-bl-HIV-1 IIIB system, MT-2-HIV-1 IIIB system, and peripheral blood mononuclear cells (PBMCs)-HIV-1 BaL system. The 50% inhibitory concentrations (IC 50) of K-41A on HIV-1 replication in three systems were 0.75 μM, 0.09 μM, and 0.13 μM, respectively, and the selective indexes (SIs) were 5.81, 49.44, and 598.00, respectively. The IC 50 of K-41Am in three systems were 5.57 μM, 0.24 μM, and 1.15 μM, respectively, and the SIs were > 1.04, 80.71, and > 5.03, respectively. Results: Mechanism research demonstrates that two compounds inhibited the activities of HIV-1 reverse transcriptase (RT) and integrase (IN) in a dose-dependent manner. Molecular docking shows that the docking scores were relatively high between the compound and HIV-1 RT or IN. Conclusions: K-41A and K-41Am possess anti-HIV-1 activity via a multi-target inhibition mechanism, which provides a novel molecular pattern for anti-HIV drug design and structural modification to improve the anti-HIV activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polyether antibiotics K-41A and K-41Am inhibit HIV-1 replication via suppressing the activities of HIV-1 reverse transcriptase and integrase

et al. 2020

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“…The most common type of dual inhibitors are those that target IN and RNase H of RT, which share a common catalytic site residues and geometry [ 75 , 133 ]. Both sites have a common αβ-fold that contains a central five-stranded mixed β-sheet next to α-helices on each side.…”

Section: Inis Approved For Clinical Applicationmentioning

confidence: 99%

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Choi

Mallareddy

et al. 2018

Future Sci. OA

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AIDS caused by the infection of HIV is a prevalent problem today. Rapid development of drug resistance to existing drug classes has called for the discovery of new targets. Within the three major enzymes (i.e., HIV-1 protease, HIV-1 reverse transcriptase and HIV-1 integrase [IN]) of the viral replication cycle, HIV-1 IN has been of particular interest due to the absence of human cellular homolog. HIV-1 IN catalyzes the integration of viral genetic material with the host genome, a key step in the viral replication process. Several novel classes of HIV IN inhibitors have been explored by targeting different sites on the enzyme. This review strives to provide readers with updates on the recent developments of HIV-1 IN inhibitors.

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“…Recently, a few chemical classes of NNRTI compounds have shown dual inhibition, and thus, designing multitarget inhibitors is of current interest in HIV research . However, a detailed analysis of these compounds is beyond the scope of the paper, and thus, only a few representative examples are discussed.…”

Section: Evolution Of Nnrti Scaffoldsmentioning

confidence: 99%

Integrative approaches in HIV‐1 non‐nucleoside reverse transcriptase inhibitor design

Poongavanam

Namasivayam

Vanangamudi

et al. 2017

WIREs Comput Mol Sci

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The design of inhibitors for human immunodeficiency virus type-1 reverse transcriptase (HIV-1 RT) is one of the most successful approaches for the treatment of HIV infections. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a prominent drug class, which includes nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine approved for clinical use. However, the efficiency of many of these drugs has been undermined by drug-resistant variants of HIV-1 RT, and it therefore becomes inevitable to design novel drugs to cope with resistance. Here, we discuss various drug design strategies, which include traditional medicinal chemistry, computational chemistry, and chemical biology approaches. In particular, computational modeling approaches, including machine learning, empirical descriptors-based, force-field, ab initio, and hybrid quantum mechanics/molecular mechanics-based methods are discussed in detail. We foresee that these methods will have a major impact on efforts to guide the design and discovery of the next generation of NNRTIs that combat RT multidrug resistance.

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Advances in rationally designed dual inhibitors of HIV-1 reverse transcriptase and integrase

Cited by 34 publications

References 54 publications

Polyether antibiotics K-41A and K-41Am inhibit HIV-1 replication via suppressing the activities of HIV-1 reverse transcriptase and integrase

Polyether antibiotics K-41A and K-41Am inhibit HIV-1 replication via suppressing the activities of HIV-1 reverse transcriptase and integrase

Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase

Integrative approaches in HIV‐1 non‐nucleoside reverse transcriptase inhibitor design

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