Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, JFB 824, Boston, MA 02115, USA.
Structure (Impact Factor: 5.62). 12/2008; 16(11):1689-701. DOI: 10.1016/j.str.2008.09.005
Source: PubMed

ABSTRACT Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.

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Available from: Arne Schon, Apr 25, 2014
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    • "Several recently disclosed Region III congeners exhibit both increased affinity for gp120 and improved potency against selected clade B and C viruses relative to NBD-556 [24], [25], [26]. An exploration of structure-activity relationships [27] demonstrated that variation of the Region III moiety not only influences compound binding affinity, but also modulates the capacity of NBD-derived compounds to enhance viral infectivity in cells lacking the CD4 receptor (CD4−CCR5+ Cf2Th cells) [21], an undesired trait for the development of viral entry inhibitors. Indeed, Region III analogues possessing a trans-1,2-indane and guanidinium functionality [24], [26] do not enhance CD4 independent viral entry in contrast to NBD-556, NBD-557 and other Region III analogues. "
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    ABSTRACT: Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.
    PLoS ONE 01/2014; 9(1):e85940. DOI:10.1371/journal.pone.0085940 · 3.23 Impact Factor
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    • "To verify the mode of anti-viral action, the infection inhibitory of IMOD was investigated and compared for murine leukemia virus (MLV) as well of HIV-1 using GFP reporter virions. Comparison of the result obtained from these tests shows whether inhibitory effect of IMOD for HIV-1 is specific or it could inhibit a retrovirus control as well.[32] The infection process of both retroviruses (HIV-1 and MLV) was inhibited with IC50 values of 6 × 10-4V/V and 4.9 × 10-4V/V, respectively. "
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    ABSTRACT: Setarud (IMOD™) is a herbal medicine with beneficial effect for patients suffering Human immunodeficiency virus (HIV) infection and has been approved for IV (intra venues) injection. The beneficial effect of IMOD administration for acquired immune deficiency syndrome (AIDS) patient has been proved in previous clinical trials. Here the in vitro inhibitory effect of IMOD against HIV-1, Herpes simplex virus (HSV) and murine leukemia viruses (MLV) was evaluated. HIV single cycle replication and HSV plaque reduction assays were used to evaluate the anti-viral effect. The level of HIV replication was monitored by p24 capture Enzyme-linked immunosorbent assay (ELISA). The single round infection [with green fluorescent protein (GFP) reporter MLV and HIV], virucidal and time-of-additions (HSV) assays were utilized to determine the mode of anti-viral activity. The toxicity of IMOD for cells was monitored by XTT (sodium 3_-[1 (phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4-methoxy-6-nitro)benzene sulfonic acid) cell proliferation assay kit. IMOD inhibited 50% of HIV-1 and HSV replication (IC(50)) at 6.5 × 10(-4) and 4.3 × 10(-3)V/V concentrations, respectively. The IC(50) value against HIV-1 and MLV infection were 6 × 10(-4)V/V and 4.9 × 10(-4)V/V. Virucidal assay showed that IMOD reduces the potency of HIV and HSV particles to 41 and 54% of control, respectively. Time-of-addition study revealed that IMOD inhibits the replication of HSV at a stage after penetration of virions to the target cells. Data from this study indicate that IMOD has significant anti-viral activity against HIV, HSV and MLV. Setarud could be subjected to further investigation after isolation of the constituents and determination of the toxic components.
    Indian Journal of Pharmacology 07/2012; 44(4):448-53. DOI:10.4103/0253-7613.99301 · 0.69 Impact Factor
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    • "CD4 mimetic compounds, also called miniCD4s, constitute a very promising class of CD4bs inhibitors, e.g. M48 and M48U1 [23,33-38]. Upon binding with HIV-1 and similarly to the cellular CD4 receptor, M48 and M48U1 induce conformational changes in the gp120 architecture thereby exposing masked epitopes on the envelope protein. "
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    ABSTRACT: Binding of the viral envelope protein (Env), and particularly of its gp120 subunit, to the cellular CD4 receptor is the first essential step of the HIV-1 entry process. The CD4 binding site (CD4bs) of gp120, and especially a recessed cavity occupied by the CD4 Phe43 residue, are known to be highly conserved among the different circulating subtypes and therefore constitute particularly interesting targets for vaccine and drug design. The miniCD4 proteins are a promising class of CD4bs inhibitors. Studying virus evolution under pressure of CD4bs inhibitors could provide insight on the gp120-CD4 interaction and viral entry. The present study reports on the resistance induction of two subtype B HIV-1 against the most active miniCD4, M48U1, and its ancestor, M48, and how these mutated positions affect CD4bs recognition, entry efficiency, and sensitivity to other CD4bs inhibitors. Resistance against M48U1 was always associated with S375R/N substitution in both BaL and SF162; M48 resistance was associated with D474N substitution in SF162 and with H105Y substitution in BaL. In addition, some other mutations at position V255 and G471 were of importance for SF162 resistant viruses. Except for 474, all of these mutated positions are conserved, and introducing them into an SF162 Env expressing infectious molecular clone (pBRNL4.3 SF162) resulted in decreased entry efficiency. Furthermore, resistant mutants showed at least some cross-resistance towards other CD4bs inhibitors, the V3 monoclonal antibody 447-52D and some even against the monoclonal antibody 17b, of which the epitope overlaps the co-receptor binding site. The mutations H105Y, V255M, S375R/N, G471R/E, and D474N are found to be involved in resistance towards M48 and M48U1. All mutated positions are part of, or in close proximity to, the CD4bs; most are highly conserved, and all have an impact on the entry efficiency, suggesting their importance for optimal virus infectivity.
    Retrovirology 05/2012; 9(1):36. DOI:10.1186/1742-4690-9-36 · 4.19 Impact Factor
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