Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket

Stewart, Kent D.; Huth, Jeffrey R.; Ng, Teresa I.; McDaniel, Keith F.; Hutchinson, Rebecca; Stoll, V.S.; Mendoza, Renaldo; Matayoshi, Edmund D.; Carrick, Robert J.; Mo, Hongmei; Severin, Jean M.; Walter, Karl A.; Richardson, Paul L.; Barrett, Leo W.; Meadows, Robert P.; Anderson, Steve; Kohlbrenner, William E.; Maring, Clarence J.; Kempf, Dale J.; Molla, Akhter; Olejniczak, Edward T.

doi:10.1016/j.bmcl.2009.11.076

Cited by 28 publications

(33 citation statements)

References 23 publications

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“…In vitro screening has identified competitive inhibitors of assembly of the gp41 HR1-and HR2-derived peptides into the 6HB. [13][14][15][16][17][18][19][20][21][22][23][24] HTS for smallmolecule inhibitors competing with the chemokine (RANTES) binding to CCR5 has led to the identification of identified coreceptor antagonists that effectively blocked fusion of CCR5-tropic viruses: maraviroc, Sch-C, and TAK-779. [10][11][12] These narrowly focused readouts provide a powerful means to identify specific inhibitors of a given step of the virus entry, but exclude all other targets for inhibition of HIV-1 fusion.…”

Section: Introductionmentioning

confidence: 99%

“…In the final 6-helix bundle structure (6HB), three HR1 and three HR2 coalesce forming a highly stable antiparallel helical bundle. A number of small-molecule inhibitors of HIV-1 fusion that interfere with CD4-induced conformational changes in gp120, 8,9 coreceptor binding, [10][11][12] and the gp41 6HB formation [13][14][15][16][17][18][19][20][21][22][23][24] have been identified by high-throughput screening (HTS). Currently, only two HIV-1 fusion inhibitors (enfuvirtide and maraviroc) have been approved for clinical use.…”

Section: Introductionmentioning

confidence: 99%

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High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

Marin

Giroud

et al. 2015

ASSAY and Drug Development Technologies

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HIV-1 initiates infection by merging its envelope membrane with the target cell membrane, a process that is mediated by the viral Env glycoprotein following its sequential binding to CD4 and coreceptors, CXCR4 or CCR5. Although HIV-1 fusion has been a target for antiviral therapy, the virus has developed resistance to drugs blocking the CCR5 binding or Env refolding steps of this process. This highlights the need for novel inhibitors. Here, we adapted and optimized an enzymatic HIV-cell fusion assay, which reports the transfer of virus-encapsulated b-lactamase into the cytoplasm, to high-throughput screening (HTS) with a 384-well format. The assay was robustly performed in HTS format and was validated by the pilot screen of a small library of pharmacologically active compounds. Several hits identified by screening included a prominent cluster of purinergic receptor antagonists. Functional studies demonstrated that P2X1 receptor antagonists selectively inhibited HIV-1 fusion without affecting the fusion activity of an unrelated virus that enters cells through an endocytic route. The inhibition of HIV-cell fusion by P2X1 antagonists was not through downmodulation of the cell surface expression of CD4 or coreceptors, thus implicating P2X1 receptor in the HIV-1 fusion step. The ability of these antagonists to inhibit viruses regardless of their coreceptor (CXCR4 or CCR5) preference indicates that fusion is blocked at a late step downstream of coreceptor binding. A future large-scale screening campaign for HIV-1 fusion inhibitors, using the above functional readout, will likely reveal novel classes of inhibitors and suggest potential targets for antiviral therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

Marin

Giroud

et al. 2015

ASSAY and Drug Development Technologies

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“…These complexes were identified from recent publications (Stewart et al , 2010; Wells and McClendon, 2007) and PPI databases (Bourgeas et al , 2010; Higueruelo et al , 2009) and are shown in Table 1. These complexes did not appear in the training set because the inhibitor was not present in the binding affinity databases or a sufficiently homologous complex was not available in the non-redundant subset.…”

Section: Methodsmentioning

confidence: 99%

“…PPIs were identified from the literature (Bourgeas et al , 2010; Higueruelo et al , 2009; Stewart et al , 2010; Wells and McClendon, 2007) and only inhibitors with known structure that bind at the PPI interface are considered. The number of SMISPs predicted by our combined classifier is shown with the total number of clusters evaluated.…”

Section: Methodsmentioning

confidence: 99%

Small-molecule inhibitor starting points learned from protein–protein interaction inhibitor structure

Koes

Camacho

2011

Bioinformatics

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Motivation: Protein–protein interactions (PPIs) are a promising, but challenging target for pharmaceutical intervention. One approach for addressing these difficult targets is the rational design of small-molecule inhibitors that mimic the chemical and physical properties of small clusters of key residues at the protein–protein interface. The identification of appropriate clusters of interface residues provides starting points for inhibitor design and supports an overall assessment of the susceptibility of PPIs to small-molecule inhibition.Results: We extract Small-Molecule Inhibitor Starting Points (SMISPs) from protein-ligand and protein–protein complexes in the Protein Data Bank (PDB). These SMISPs are used to train two distinct classifiers, a support vector machine and an easy to interpret exhaustive rule classifier. Both classifiers achieve better than 70% leave-one-complex-out cross-validation accuracy and correctly predict SMISPs of known PPI inhibitors not in the training set. A PDB-wide analysis suggests that nearly half of all PPIs may be susceptible to small-molecule inhibition.Availability: http://pocketquery.csb.pitt.edu.Contact: dkoes@pitt.eduSupplementary information: Supplementary data are available at Bioinformatics online.

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“…Stewart et al at Abbott Laboratories [120] used NMR screening to identify anti-HIV-1 benzamide, compound 1, which inhibited HIV-1 Env-mediated cell-cell fusion with an IC 50 of 14 μM (Fig. 3c).…”

Section: Small-molecule Hiv Entry Inhibitors Target Gp41mentioning

confidence: 99%

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

Lu¹,

Yu²,

Cai³

et al. 2015

CTMC

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Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development.

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Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket

Cited by 28 publications

References 23 publications

High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

Small-molecule inhibitor starting points learned from protein–protein interaction inhibitor structure

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41

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