Downsizing a human inflammatory protein to a small molecule with equal potency and functionality

Reid, Robert C.; Yau, Mei-Kwan; Singh, Ranee; Hamidon, Johan K.; Reed, Anthony N.; Chu, Peifei; Suen, Jacky Y.; Stoermer, Martin J.; Blakeney, Jade S.; Lim, Junxian; Faber, Jonathan M.; Fairlie, David P.

doi:10.1038/ncomms3802

Cited by 33 publications

(71 citation statements)

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“…This study represents a major step toward understanding the molecular mechanism for activation of TLQP-21 and paves the way for designing new agonists/antagonists to modulate the function of the C3aR1 receptor (Reid et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism

Cero¹,

Vostrikov²,

Verardi³

et al. 2014

Structure

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SUMMARY TLQP-21, a VGF-encoded peptide is emerging as a novel target for obesity-associated disorders. TLQP-21 is found in the sympathetic nerve terminals in the adipose tissue and targets the G-protein-coupled-receptor (GPCR) Complement-3a-Receptor1 (C3aR1). So far, the mechanisms of TLQP-21-induced receptor activation remained unexplored. Here, we report that TLQP-21 is intrinsically disordered and undergoes a disorder-to-order transition, adopting an α-helical conformation, upon targeting cells expressing the C3aR1. We determined that the hot spots for TLQP-21 are located at the C-terminus, with mutations in the last four amino acids progressively reducing the bioactivity and, a single site mutation (R21A) or C-terminal amidation abolishing its function completely. Interestingly, the human TLQP-21 sequence carrying a S20A substitution activates the human C3aR1 receptor with lower potency compared to the rodent sequence. These studies reveal the mechanism of action of TLQP-21 and provide molecular templates for designing agonists and antagonists to modulate C3aR1 functions.

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Section: Discussionmentioning

confidence: 99%

The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism

Cero¹,

Vostrikov²,

Verardi³

et al. 2014

Structure

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show abstract

“…For instance, one of the benefits of utilizing small molecules is that they are unlikely to pose a significant issue regarding immunogenicity since their molecular sizes are too small to elicit an A c c e p t e d M a n u s c r i p t immune response effectively [197]. In addition, small molecules are often inexpensive and chemically stable when compared to recombinant protein growth factors [198]. It should be noted that the molecular weights of small molecules are less than 1,000 Daltons; therefore, many of them are able to diffuse into cells and interact with specific intracellular protein receptors.…”

Section: Small Molecule Deliverymentioning

confidence: 99%

Electrospinning of polymer nanofibers for tissue regeneration

Jiang

Carbone

et al. 2015

Progress in Polymer Science

431

242

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Repair and regeneration of human tissues and organs using biomaterials, cells, and/or growth factors is a great challenge for tissue engineers and surgeons. The convergence of advanced materials science, nanotechnology, stem cell science, and developmental biology, which we define as Regenerative Engineering, represents the next multidisciplinary paradigm to engineer complex tissues. One of the grand challenges in this field is to mimic closely the hierarchical architecture and properties of the extracellular matrices (ECM) of the native tissues.A bio-inspired approach to creating biomaterials with nanoscale topographical features, microand macroscale gradient structures, and biological domains to interact with target growth factors and cells is key to overcoming this challenge for successful tissue regeneration. Furthermore, the healing and repair of diseased musculoskeletal tissues rely on many signaling pathways, involving numerous growth factors and their receptors. Thus, pharmacological manipulation of the signaling pathways with bioactive molecules is an important component of tissue regeneration. This review summarizes current strategies to develop advanced nanofibrous polymer-based scaffolds via electrospinning, their applications in regenerating human musculoskeletal tissues, and the use of polymer nanofibers to deliver growth factors or small molecules for regenerative medicine.

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“…For example, a hydrogen-bond accepting nitrogen conferred agonist activity, with much greater potency for imidazoles and oxazoles ( Figure 3) than for oxadiazoles, furans and other heterocycles. Interestingly, there was a linear correlation [9,10] between the C3aR-binding affinity (measured by competition with 125 I-C3a) and the calculated hydrogen-bond acceptor interaction energy (kcal mol -1 ) between water and heteroatom of heterocycles compared with the water dimer (determined using ab initio methods MP2/6-311++G(3d,3p) and corrected for the basis set superimposition error within Gaussian 09). This enabled us to tune agonist potency by rational variation of the heterocyclic component incorporated into the dipeptide mimetics, coupled with changes to other substituents.…”

Section: Fig 2 Heterocyclic Dipeptide Mimetics Derived From Dipeptimentioning

confidence: 99%

“…Here we summarize the principle and effectiveness of this idea, which starts with a functionally important amino acid in C3a and rationally grows it into functional surrogates for C3a. We compare activity profiles for the resulting peptidomimetics versus human C3a, all compounds binding to a specific G protein coupled receptor (C3aR) expressed on the plasma membrane surface of human immune and other cell types [9,10].…”

Section: Introductionmentioning

confidence: 99%