Downsizing antibodies: Towards complementarity-determining region (CDR)-based peptide mimetics

holsbeeck, Kevin Van; Martins, José; Ballet, Steven

doi:10.1016/j.bioorg.2021.105563

Cited by 26 publications

(30 citation statements)

References 150 publications

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“…Nevertheless, the effect was modest when compared to Nb80 inhibitory effect. These attempts still need more efforts for success, probably because peptidomimetics for ADRB2 fail to fully stabilize active conformations of the receptor ( 103 , 104 ).…”

Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Intracellular VHHs to monitor and modulate GPCR signaling

et al. 2022

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Single-domain antibody fragments, also known as VHHs or nanobodies, have opened promising avenues in therapeutics and in exploration of intracellular processes. Because of their unique structural properties, they can reach cryptic regions in their cognate antigen. Intracellular VHHs/antibodies primarily directed against cytosolic proteins or transcription factors have been described. In contrast, few of them target membrane proteins and even less recognize G protein-coupled receptors. These receptors are major therapeutic targets, which reflects their involvement in a plethora of physiological responses. Hence, they elicit a tremendous interest in the scientific community and in the industry. Comprehension of their pharmacology has been obscured by their conformational complexity, that has precluded deciphering their structural properties until the early 2010’s. To that respect, intracellular VHHs have been instrumental in stabilizing G protein-coupled receptors in active conformations in order to solve their structure, possibly bound to their primary transducers, G proteins or β-arrestins. In contrast, the modulatory properties of VHHs recognizing the intracellular regions of G protein-coupled receptors on the induced signaling network have been poorly studied. In this review, we will present the advances that the intracellular VHHs have permitted in the field of GPCR signaling and trafficking. We will also discuss the methodological hurdles that linger the discovery of modulatory intracellular VHHs directed against GPCRs, as well as the opportunities they open in drug discovery.

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Section: Therapeutic Opportunitiesmentioning

confidence: 99%

Intracellular VHHs to monitor and modulate GPCR signaling

et al. 2022

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“…15-50 kDa) such as antigen-binding fragments (Fab), single-chain variable fragments (scFv) and recombinant variable single domains such as Nanobodies (Nb) [1]. In addition, smaller synthetic peptides based on (parts of) the antigen-binding site of antibodies or Nanobodies have been investigated as antibody mimetics, although so far with limited success [2].…”

Section: Introductionmentioning

confidence: 99%

Downsizing Nanobodies: Towards CDR Loop Mimetics Modulating Intracellular Protein-Protein Interactions

holsbeeck¹,

Fischer²,

González³

et al. 2022

Proceedings of the 36th European and the 12th International Peptide Symposium

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“…6 Yet, reports of nanobody-based peptidomimetics are limited. 3 As one of their many interesting applications, nanobodies emerged as useful tools to stabilize conformationally flexible proteins 7 and protein-protein complexes, 8 such as the recent discovery of nanobodies modulating the RAS:SOS1 protein complex. 9 RAS proteins are small G proteins regulating important intracellular signaling networks by functioning as binary molecular switches.…”

mentioning

confidence: 99%

“…2 Smaller synthetic peptides based on these antibodies’ crucial complementarity-determining regions (CDR) have also been investigated as antibody miniatures, but they frequently show significantly lowered potencies (µM-mM). 3 Optimization seldomly leads to potent peptidomimetics with biological activities comparable to the native antibody. 4…”

mentioning

confidence: 99%

“…2 Smaller synthetic peptides based on these antibodies' crucial complementarity-determining regions (CDR) have also been investigated as antibody miniatures, but they frequently show significantly lowered potencies (µM-mM). 3 Optimization seldomly leads to potent peptidomimetics with biological activities comparable to the native antibody. 4 The advent and success of nanobodies (Nbs, ~15kDa) represents a rather untapped alternative source of CDR-based paratopes for the development of low molecular weight (≤2kDa) antibody mimetics.…”

mentioning

confidence: 99%

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Nanobody CDR3 mimetics enhance SOS1-catalyzed nucleotide exchange on RAS

holsbeeck

Fischer

González

et al. 2022

Preprint

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RAS proteins control various intracellular signaling networks. Mutations at specific locations were shown to stabilize their active GTP-bound state, which is associated with the development of multiple cancers. An attractive approach to modulate RAS signaling is through its regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). With the recent discovery of Nanobody14, which potently enhances SOS1-catalyzed nucleotide exchange on RAS, we explored the feasibility of developing peptide mimetics by structurally mimicking the complementarity-determining region 3 (CDR3). Guided by a biochemical GEF assay and X-ray co-crystal structures, successive rounds of optimization and gradual conformational rigidification led to CDR3 mimetics showing half of the maximal activation potential of the native nanobody. Altogether, this study provides the first proof-of-concept that peptides able to functionally modulate a protein-protein interaction can be obtained by structural mimicry of a nanobody paratope.

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Downsizing antibodies: Towards complementarity-determining region (CDR)-based peptide mimetics

Cited by 26 publications

References 150 publications

Intracellular VHHs to monitor and modulate GPCR signaling

Intracellular VHHs to monitor and modulate GPCR signaling

Downsizing Nanobodies: Towards CDR Loop Mimetics Modulating Intracellular Protein-Protein Interactions

Nanobody CDR3 mimetics enhance SOS1-catalyzed nucleotide exchange on RAS

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