Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization

LaLonde, Judith M.; Le-Khac, Matthew; Jones, David M.; Courter, Joel R.; Park, Jongwoo; Schön, Arne; Princiotto, Amy M.; Wu, Xueling; Mascola, John R.; Freire, Ernesto; Sodroski, Joseph; Madani, Navid; Hendrickson, Wayne A.; Smith, Amos B.

doi:10.1021/ml300407y

Cited by 55 publications

(93 citation statements)

References 26 publications

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“…sCD4 and the miniprotein M48U1 were produced and purified as previously described (26,52). The CD4-mimetic small molecules JP-III-48 and DMJ-I-228 were synthesized as described previously (20,21). The compounds were analyzed, dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM, aliquoted, and stored at −20°C.…”

Section: Methodsmentioning

confidence: 99%

“…The prototypes of such compounds, NBD-556 and NBD-557, were discovered in a screen for inhibitors of gp120-CD4 interaction (19). These small-molecule ∼337-Da compounds and recent derivatives (DMJ-I-228, JP-III-48) bind in the Phe-43 cavity (20)(21)(22), a highly conserved ∼150-Å 3 pocket in the gp120 glycoprotein located at the interface of the inner domain, outer domain, bridging sheet, and CD4 receptor (23). CD4mc block gp120-CD4 interaction and induce thermodynamic changes in gp120 similar to those observed during CD4 or soluble CD4 (sCD4) binding (24).…”

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confidence: 99%

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CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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128

291

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HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Richard

Veillette

Brassard

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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128

291

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“…4,5 Like the initial congeners reported by Debnath et al (see 1 and 2, Figure 1), 6−8 3 binds the Phe43 cavity of the viral envelope (Env) glycoprotein gp120, blocking CD4 binding and triggering a conformational change that ultimately results in viral inactivation.…”

mentioning

confidence: 85%

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Melillo

Liang

Park

et al. 2016

ACS Med. Chem. Lett.

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157

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The optimization, based on computational, thermodynamic, and crystallographic data, of a series of small-molecule ligands of the Phe43 cavity of the envelope glycoprotein gp120 of human immunodeficiency virus (HIV) has been achieved. Importantly, biological evaluation revealed that the small-molecule CD4 mimics (4−7) inhibit HIV-1 entry into target cells with both significantly higher potency and neutralization breadth than previous congeners, while maintaining high selectivity for the target virus. Their binding mode was characterized via thermodynamic and crystallographic studies.

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“…NBD-556 binds in a well-conserved pocket on gp120 and can induce conformational changes in gp120 similar to those induced by CD4 (88)(89)(90)(91). Structure-based design has led to the improvement of the affinity and antiviral potency and breadth of the CD4-mimetic compounds (92)(93)(94)(95). Recently developed analogues have been shown to inhibit infection by a range of HIV-1 primary strains (94,95).…”

mentioning

confidence: 99%

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

Madani

Princiotto

Easterhoff

et al. 2016

J Virol

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The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

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Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-ray and Thermodynamic Characterization

Cited by 55 publications

References 26 publications

CD4 mimetics sensitize HIV-1-infected cells to ADCC

CD4 mimetics sensitize HIV-1-infected cells to ADCC

Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

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