A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Lin, Pin‐Fang; Blair, Wade; Wang, Tao; Spicer, Timothy; Guo, Qi; Zhou, Nannan; Gong, Yi-Fei; Wang, H.-G. Heidi; Rose, Ronald E.; Yamanaka, Gregory; Robinson, Brett S.; Li, Changben; Fridell, Robert A.; Deminie, Carol; Demers, G W; Yang, Zheng; Zadjura, Lisa; Meanwell, Nicholas A.; Colonno, Richard J.

doi:10.1073/pnas.1832214100

Cited by 342 publications

(314 citation statements)

References 33 publications

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“…The sublibraries of interest were randomized by amplification via error-prone PCR (41), using a dNTP-Mutagenesis Kit (Jena Biosciences) including 50 M each of the nucleotide analogs 8-oxo-2=-dGTP (8-oxo-dGTP) and 6-(2-deoxy-␤-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido- [4,5-c] [1,2]oxazin-7-one-triphosphate (dPTP) in the RT-PCR of ribosome display. For the subsequent panning round, a one-to-one mixture of error-prone and original PCR products was used as a template for RNA transcription.…”

Section: Reagentsmentioning

confidence: 99%

“…The potential of HIV entry-blocking agents for intervention strategies has been acknowledged for a long time, and a number of agents targeting the viral envelope proteins and the cellular receptor CD4, CCR5, or CXCR4 have been developed (2,3). However, thus far, only two entry inhibitors, the peptidic fusion inhibitor T-20, targeting gp41 (4), and the small-molecule CCR5 inhibitor maraviroc (5), have been used clinically.…”

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confidence: 99%

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Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors

Mann

Friedrich

Krarup

et al. 2013

J Virol

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Here, we applied the designed ankyrin repeat protein (DARPin) technology to develop novel gp120-directed binding molecules with HIV entry-inhibiting capacity. DARPins are interesting molecules for HIV envelope inhibitor design, as their high-affinity binding differs from that of antibodies. DARPins in general prefer epitopes with a defined folded structure. We probed whether this capacity favors the selection of novel gp120-reactive molecules with specificities in epitope recognition and inhibitory activity that differ from those found among neutralizing antibodies. The preference of DARPins for defined structures was notable in our selections, since of the four gp120 modifications probed as selection targets, gp120 arrested by CD4 ligation proved the most successful. Of note, all the gp120-specific DARPin clones with HIV-neutralizing activity isolated recognized their target domains in a conformation-dependent manner. This was particularly pronounced for the V3 loop-specific DARPin 5m3_D12. In stark contrast to V3-specific antibodies, 5m3_D12 preferentially recognized the V3 loop in a specific conformation, as probed by structurally arrested V3 mimetic peptides, but bound linear V3 peptides only very weakly. Most notably, this conformation-dependent V3 recognition allowed 5m3_D12 to bypass the V1V2 shielding of several tier 2 HIV isolates and to neutralize these viruses. These data provide a proof of concept that the DARPin technology holds promise for the development of HIV entry inhibitors with a unique mechanism of action.

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Section: Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors

Mann

Friedrich

Krarup

et al. 2013

J Virol

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“…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%

“…Infectivity-based HTS for fusion inhibitors identified BMS-806 that interferes with CD4-induced conformational changes in gp120 8,9 as well as several postfusion inhibitors. 36 An important caveat of infectivity-based screens when searching for viral fusion inhibitors is that they produce a large number of hits targeting postfusion steps of HIV-1 entry, thus complicating data analysis and hit validation.…”

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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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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“…BMS-378806, a 4-methoxy-7-azaindole derivative, inhibits infection by both laboratory and clinical HIV-1 strains at nanomolar levels. Lin et al [103] have demonstrated that BMS-378806-induced mutations are localized at, or near, the CD4-binding pocket of gp120 and BMS-378806 binds to gp120, thereby blocking attachment of the virus to CD4. However, Si et al [104] have suggested that BMS-378806 does not directly block gp120 from binding to CD4, but instead interferes with CD4-induced conformational rearrangement of gp120egp41.…”

Section: Hiv-1 Gp120 Inhibitorsmentioning

confidence: 99%

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

Teixeira

Gomes

et al. 2011

European Journal of Medicinal Chemistry

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A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Cited by 342 publications

References 33 publications

Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors

Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors

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

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

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