Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Sato, Shinichi; Inokuma, Takao; Otsubo, Nobumasa; Burton, Dennis R.; Barbas, Carlos F.

doi:10.1021/ml400097z

Cited by 16 publications

(19 citation statements)

References 40 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because this methoxy function is completely buried within the protein interior in both Orientations 1 and 2, this observation might suggest that the energy difference between Orientations 1/2 and Orientation 3 is larger for the indole than the azaindole series. Similar activity trends were observed in recent work by Sato, et al 19 in which 1 and a related analog, BMS-488043, were conjugated to aldolase antibody 38C2 in an effort to enhance HIV fusion inhibition. Consistent with our model, conjugation could occur at multiple positions, with the most significant activity impairmemt occuring through conjugation at the C4 site on 1 .…”

Section: Resultssupporting

confidence: 83%

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

et al. 2014

View full text Add to dashboard Cite

Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.

show abstract

Section: Resultssupporting

confidence: 83%

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The proposed binding site for BMS‐626529 within the gp120 water channel/CD4:F43 binding site of the gp120 LIG, pCD4, and bCD4 models did not accommodate the entire spectrum of structural motifs shown in Figure (specifically, the 4‐(diphenylmethylene) piperidine and the C7 2‐amino‐benzimidazole carboxamide moieties). In addition, the BMS‐488043 C7‐antibody conjugates described by Sato et al . and the 4′‐methoxy indole attachment inhibitor with a C‐7 furanyl PEG‐DNP are not compatible with the model of AI binding within the gp120 water channel/CD4:F43 binding pocket in the gp120 LIG, pCD4, and bCD4 models.…”

Section: Resultsmentioning

confidence: 89%

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

et al. 2014

View full text Add to dashboard Cite

HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure–activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20–β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the “open state” four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development. Proteins 2015; 83:331–350. © 2014 Wiley Periodicals, Inc.

show abstract

“…The conjugation is based on the derivatization of the pharmacophore with either a diketone, vinylketone or azetidinone functional group that forms a covalent bond with a specific lysine residue in the active site of the catalytic antibody ( Figure 8B). This technology has been extensively exploited to develop a variety of novel therapeutics for cancer [171][172][173][174][175][176][177][178], HIV [179], influenza [180], pain [181] or growth hormone (GH) deficiency [182]. It must be reiterated, though, that it is no longer the targeting properties of the antibody that are desired, but their pharmacokinetic characteristics, and, hence, these are not antibody conjugates in the classical sense.…”

Section: Catalytic Antibodiesmentioning

confidence: 99%

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

2015

View full text Add to dashboard Cite

Monoclonal antibodies (mAbs) and their derivatives are currently the fastest growing class of therapeutics. Even if naked antibodies have proven their value as successful biopharmaceuticals, they suffer from some limitations. To overcome suboptimal therapeutic efficacy, immunoglobulins are conjugated with toxic payloads to form antibody drug conjugates (ADCs) and with chelating systems bearing therapeutic radioisotopes to form radioimmunoconjugates (RICs). Besides their therapeutic applications, antibody conjugates are also extensively used for many in vitro assays. A broad variety of methods to functionalize antibodies with various payloads are currently available. The decision as to which conjugation method to use strongly depends on the final purpose of the antibody conjugate. Classical conjugation via amino acid residues is still the most common method to produce antibody conjugates and is suitable for most in vitro applications. In recent years, however, it has become evident that antibody conjugates, which are generated via site-specific conjugation techniques, possess distinct advantages with regard to in vivo properties. Here, we give a comprehensive overview on existing and emerging strategies for the production of covalent and non-covalent antibody conjugates.

show abstract

Chemically Programmed Antibodies As HIV-1 Attachment Inhibitors

Cited by 16 publications

References 40 publications

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Antibody Conjugates: From Heterogeneous Populations to Defined Reagents

Contact Info

Product

Resources

About