Peptide Paratope Mimics of the Broadly Neutralizing HIV‐1 Antibody b12

Haußner, Christina; Damm, Dominik; Nirschl, Sandra; Rohrhofer, Anette; Schmidt, Bárbara; Eichler, Jutta

doi:10.1002/cbic.201600621

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…The coactivator peptide with the sequence KHKILHRLLQDSSS corresponding to residues 686–699 of the SRC-2 protein (UNIPROT entry Q15596) was N-terminally acetylated and C-terminally amidated 3 , 48 . The peptide was synthesized using Fmoc-based solid-phase synthesis, as previously described 49 . For the measurements in presence of effectors, the protein variant was incubated first with either solid powder of estradiol or raloxifene for 16 h at 16 °C while gently agitating.…”

Section: Methodsmentioning

confidence: 99%

A PROSS-designed extensively mutated estrogen receptor α variant displays enhanced thermal stability while retaining native allosteric regulation and structure

Kriegel

Wiederanders

Alkhashrom

et al. 2021

Sci Rep

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Protein stability limitations often hamper the exploration of proteins as drug targets. Here, we show that the application of PROSS server algorithms to the ligand-binding domain of human estrogen receptor alpha (hERα) enabled the development of variant ERPRS* that comprises 24 amino acid substitutions and exhibits multiple improved characteristics. The protein displays enhanced production rates in E. coli, crystallizes readily and its thermal stability is increased significantly by 23 °C. hERα is a nuclear receptor (NR) family member. In NRs, protein function is allosterically regulated by its interplay with small molecule effectors and the interaction with coregulatory proteins. The in-depth characterization of ERPRS* shows that these cooperative effects are fully preserved despite that 10% of all residues were substituted. Crystal structures reveal several salient features, i.e. the introduction of a tyrosine corner in a helix-loop-helix segment and the formation of a novel surface salt bridge network possibly explaining the enhanced thermal stability. ERPRS* shows that prior successes in computational approaches for stabilizing proteins can be extended to proteins with complex allosteric regulatory behaviors as present in NRs. Since NRs including hERα are implicated in multiple diseases, our ERPRS* variant shows significant promise for facilitating the development of novel hERα modulators.

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Section: Methodsmentioning

confidence: 99%

A PROSS-designed extensively mutated estrogen receptor α variant displays enhanced thermal stability while retaining native allosteric regulation and structure

Kriegel

Wiederanders

Alkhashrom

et al. 2021

Sci Rep

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“…HIV infection assay : For generation of viral stocks, CEMx174 cells [42] were infected with HIV‐1 NL4–3 resulting from transfection of HIV‐1 pBRNL4–3 , [43] as described previously. [44] At peak of virus replication, supernatants were harvested, filtered through 0.22 μm pore sizes, and stored in aliquots at −80 °C. Respective dilutions of the peptides were incubated with this viral stock for 1 h prior to infection of CEMx174 SEAP cells.…”

Section: Methodsmentioning

confidence: 99%

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

et al. 2021

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With the emergence of novel viruses, the development of new antivirals is more urgent than ever. A key step in human immunodeficiency virus type 1 (HIV-1) infection is six-helix bundle formation within the envelope protein subunit gp41. Selective disruption of bundle formation by peptides has been shown to be effective; however, these drugs, exemplified by T20, are prone to rapid clearance from the patient. The incorporation of non-natural amino acids is known to improve these pharmacokinetic properties. Here, we evaluate a peptide inhibitor in which a critical Ile residue is replaced by fluorinated analogues. We characterized the influence of the fluorinated analogues on the biophysical properties of the peptide. Furthermore, we show that the fluorinated peptides can block HIV-1 infection of target cells at nanomolar levels. These findings demonstrate that fluorinated amino acids are appropriate tools for the development of novel peptide therapeutics.

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“…Molecules that mimic the CDRs of an antibody can, therefore, be expected to mimic the binding specificities of the antibody and, consequently, its effect in preventing the interaction of a disease-associated protein with its ligand [ 100 ] ( Figure 6 , right). We have recently reported on paratope mimetic peptides of the broadly neutralizing HIV-1 antibody b12 [ 101 ]. As described above, this antibody recognizes the CD4bs of the HIV-1 envelope glycoprotein gp120, and efficiently neutralizes HIV-1 infections in vitro and in vivo [ 102 ].…”

Section: Hiv-1 Vaccine Developmentmentioning

confidence: 99%

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Ringel

Vieillard

Debré

et al. 2018

Viruses

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Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.

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Peptide Paratope Mimics of the Broadly Neutralizing HIV‐1 Antibody b12

Cited by 11 publications

References 32 publications

A PROSS-designed extensively mutated estrogen receptor α variant displays enhanced thermal stability while retaining native allosteric regulation and structure

A PROSS-designed extensively mutated estrogen receptor α variant displays enhanced thermal stability while retaining native allosteric regulation and structure

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

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