Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site

Kwon, Young Do; LaLonde, Judith M.; Yang, Yongping; Elban, Mark A.; Sugawara, Akihiro; Courter, Joel R.; Jones, David M.; Smith, Amos B.; Debnath, Asim K.; Kwong, Peter D.

doi:10.1371/journal.pone.0085940

Cited by 48 publications

(69 citation statements)

References 37 publications

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“…In contrast, the HIV-1 YU2 S375A mutant was even more sensitive to BNM-III-170 than wild-type HIV-1 YU2 . These results are consistent with the expectation that the antiviral activity of CD4-mimetic compounds depends upon their interaction with the gp120 Phe 43 cavity (88,(91)(92)(93)(94)(95).…”

Section: Methodssupporting

confidence: 92%

“…In contrast, the induction of the CD4-bound state on a virus that has not yet engaged the target cell results in a shortened infectious half-life and a dramatic increase in susceptibility to neutralization by antibodies against the conserved coreceptor-binding site (14,15,76,86,96). Recent structure-based design and synthesis has increased the potency and breadth of small-molecule CD4-mimetic compounds, which can induce the CD4-bound conformation of Env (88)(89)(90)(91)(92)(93)(94)(95). Here, we demonstrate that antibodies elicited in monkeys and humans by several different Env immunogens potently neutralize primary HIV-1 treated with subneutralizing concentrations of a CD4-mimetic compound, BNM-III-170.…”

Section: Discussionmentioning

confidence: 99%

“…The prototypic CD4-mimetic compounds have been extensively modified to achieve more contacts with gp120, resulting in improvements in antiviral potency and breadth (88)(89)(90)(91)(92)(93)(94)(95). For example, nearly all clade B HIV-1 and most clade C HIV-1 variants tested can be directly inhibited by the recently developed CD4-mimetic compounds, such as BNM-III-170 and BNM-IV-147 (95).…”

Section: Discussionmentioning

confidence: 99%

“…The prototypic CD4-mimetic compounds NBD-556 and NBD-557 only weakly inhibited a few HIV-1 isolates (87)(88)(89). 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).…”

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confidence: 99%

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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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Section: Methodssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…They include soluble CD4 (sCD4), enhanced CD4 (eCD4), sCD4 miniproteins, and small-molecule CD4-mimetic compounds (CD4mc) (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). All of these inhibitors bind gp120 near the natural binding site for CD4, a well-conserved surface element adjacent to a pocket located at the interface of the gp120 inner domain, outer domain, and bridging sheet (32)(33)(34)(35)(36)(37)(38)(39). A phenylalanine residue at position 43 (Phe 43) of CD4 fills the opening of this gp120 pocket, and thus, the pocket has been designated the Phe 43 cavity (42,43).…”

mentioning

confidence: 99%

Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Madani

Princiotto

Zhao

et al. 2017

J Virol

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Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility.IMPORTANCE The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important for virus entry. Small-molecule CD4-mimetic compounds inhibit HIV-1 infection by multiple mechanisms: (i) direct blockade of the interaction between the gp120 exterior envelope glycoprotein and CD4; (ii) premature triggering of conformational changes in the envelope glycoproteins, leading to irreversible inactivation; and (iii) exposure of cryptic epitopes to antibodies, allowing virus neutralization. The consequences of the binding of the CD4-mimetic compound to the HIV-1 envelope glycoproteins depends upon how many of the three subunits of the trimer are bound and upon the propensity of the envelope glycoproteins to undergo conformational changes. Understanding the mechanistic factors that influence

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Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV‐1 Entry Inhibitor NBD‐14270

Kurkin¹,

Curreli

Iusupov³

et al. 2022

ChemMedChem

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The envelope glycoprotein gp120 of human immunodeficiency virus type 1 (HIV‐1) plays a critical role in virus entry to the cells by binding to the host cellular protein CD4. Earlier, we reported the design and discovery of a series of highly potent small‐molecule entry antagonists containing a thiazole ring (Scaffold A). Since this thiazole ring connected with an ethyl amide linkage represents the molecule‘s flexible part, we decided to explore substituting Scaffold A with two other positional isomers of the thiazole ring (Scaffold B and C) to evaluate their effect on the antiviral potency and cellular toxicity. Here we report the novel synthesis of two sets of positional thiazole isomers of the NBD‐14270 by retrosynthetic analysis approach, their anti‐HIV‐1 activity, cellular toxicity, and structure‐activity relationships. The study revealed that Scaffold A provided the best HIV‐1 inhibitors with higher potency and better selectivity index (SI).

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Crystal Structures of HIV-1 gp120 Envelope Glycoprotein in Complex with NBD Analogues That Target the CD4-Binding Site

Cited by 48 publications

References 37 publications

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

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

Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

Design, Synthesis, and Antiviral Activity of the Thiazole Positional Isomers of a Potent HIV‐1 Entry Inhibitor NBD‐14270

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