New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Tsiang, Manuel; Jones, Gregg S.; Niedziela-Majka, Anita; Kan, Elaine; Lansdon, E.B.; Huang, Wayne; Hung, Magdeleine; Samuel, Dharmaraj; Novikov, Nikolai; Xu, Yili; Mitchell, Michael; Guo, Hongyan; Babaoglu, Kerim; Liu, Xiaohong; Geleziunas, Romas; Sakowicz, Roman

doi:10.1074/jbc.m112.347534

Cited by 149 publications

(296 citation statements)

References 56 publications

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“…[33][34][35][36]. These compounds bind at the IN CCD dimer interface occupying the principal LEDGF/p75 binding pocket (12,(37)(38)(39)(40)(41)(42). Similar to LEDGF/p75 Asp-366, the ALLINI carboxylic acid hydrogen bonds with the main chain nitrogens of residues Glu-170 and His-171 of one IN subunit.…”

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

“…The ALLINI methoxy group also hydrogen bonds with the Thr-174 side chain of the same subunit, whereas the ALLINI quinoline ring extends toward another subunit to establish hydrophobic interactions. Consequently, ALLINIs exhibit a dual mode of action: they stabilize interacting IN subunits and promote higher-order protein multimerization as well as inhibit IN-LEDGF/p75 binding in vitro (37,39,43).…”

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

“…In infected cells, ALLINIs impair both the early and late stage of HIV-1 replication underscoring the multifunctional nature of IN during HIV-1 replication (12,39,44,45). When added to target cells, ALLINIs block 3Ј-processing as well as reduce LEDGF/p75-mediated integration into active transcription units (39,46).…”

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

“…When added to target cells, ALLINIs block 3Ј-processing as well as reduce LEDGF/p75-mediated integration into active transcription units (39,46). Knockdown or knock-out of endogenous LEDGF/p75 significantly enhanced the potencies of these inhibitors in target cells, suggesting that there is competition between the cellular protein and ALLINIs for binding to HIV-1 IN during early steps of viral replication (12,47,48).…”

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

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A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

Shkriabai

Dharmarajan

Slaughter

et al. 2014

Journal of Biological Chemistry

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Background: Allosteric integrase (IN) inhibitors (ALLINIs) promote aberrant protein multimerization. Results: ALLINI-2 induces protein-protein interactions, including C-terminal residues Lys-264 and Lys-266, which lead to aberrant, higher-order IN multimerization. Conclusion: The protein-protein contacts beyond the inhibitor binding site contribute to aberrant IN multimerization. Significance: Our findings provide structural clues and underscore the significance for exploiting IN multimerization as a new therapeutic target.

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Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

Section: Hiv-1 Integrase (In)mentioning

confidence: 99%

See 2 more Smart Citations

A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

Shkriabai

Dharmarajan

Slaughter

et al. 2014

Journal of Biological Chemistry

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“…This interaction targets viral integration into transcriptionally active regions of the host chromatin recognized by the LEDGF/p75 PWWP domain [17][18][19][20][21] . The important role of LEDGF/p75 in lentiviral replication triggered the development of small molecules that efficiently block HIV-1 replication, referred to as LEDGINs that target the LEDGF/p75-HIV IN interaction interface [22][23][24][25][26][27][28][29] . LEDGINs are currently under early clinical development.…”

mentioning

confidence: 99%

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

et al. 2015

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Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.

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Enzymes as Drug Targets

Meek

2021

Burger's Medicinal Chemistry and Drug Discovery

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Many drugs commonly used today to treat infectious diseases, cancers, inflammatory, cardiovascular, and metabolic diseases, are enzyme inhibitors or inactivators. Examples exist for all six classes of enzymes, but inhibitors of hydrolases, transferases, and oxidoreductases predominate. Typically, enzyme inhibitors or inactivators that progress to become drugs exert high potency toward their targets at concentrations of 100 nanomolar or less, and attending these potencies is high selectivity for their targets. Drugs that block the activity of enzymes do so by either covalent reaction with nucleophilic enzymatic residues, or by noncovalent binding. Covalent inactivation by affinity agents and mechanism‐based inactivators is generally irreversible, leading to time‐dependent loss of enzyme activity that is normally un‐recoverable. Drugs that are noncovalent enzyme inhibitors, including bi‐substrate analogs, and analogs of enzyme reaction intermediates and transition states, like their covalent counterparts, often display time‐dependent inhibition despite the absence of covalent reaction. This pseudoirreversible inhibition is manifest at nanomolar concentrations of inhibitor, and is due to the isomerization of an initial enzyme–inhibitor complex to a tighter binary complex which reverses very slowly, if at all. Natural‐product enzyme inhibitors have provided the blueprints for many drugs, including the statins, epoxomicin, and inhibitors of HIV protease. We describe herein the aforementioned types of enzyme inhibitors and inactivators that, through the application of medicinal chemistry have rendered new therapies, including case histories of many of the more important drugs that block the action of enzymes.

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New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

Cited by 149 publications

References 56 publications

A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

A Critical Role of the C-terminal Segment for Allosteric Inhibitor-induced Aberrant Multimerization of HIV-1 Integrase

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

Enzymes as Drug Targets

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