TRPV1: A Target for Rational Drug Design

Carnevale, Vincenzo; Rohács, Tibor

doi:10.3390/ph9030052

Cited by 100 publications

(95 citation statements)

References 158 publications

(221 reference statements)

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“…So far, the results have been disappointing. In general, efficacy of TRPV1 antagonists in clinically-relevant pain conditions in humans has been modest, and there are two problematic adverse on-target effects seen with many of the compounds: reduced sensitivity to noxious heat, potentially leading to accidental burns, and an increase in body temperature, likely reflecting participation by TRPV1 channels in normal temperature regulation 139–141 . These issues, along with modest efficacy, have resulted in discontinuation of most programs.…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

“…Such “modality-specific antagonists” are based on evidence that vanilloid ligands like capsaicin (and perhaps endogenous agents mediating pain) activate TRPV1 in a different way than temperature or pH and that these modalities of activation can be differentially inhibited 141–143 . NEO6860 (Neomed) is one such modality-specific agent 144 and is currently in Phase II trials for osteoarthritis.…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

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Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

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Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

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Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

View full text Add to dashboard Cite

show abstract

“…Focusing on the nature of the TRPV1 receptor itself—multimodality with respect to different stimuli and the selection of successful combination of such factors of TRPV1 regulation as antagonist, effective dose, pH, temperature control, way of delivery, etc. [46,47]—will certainly contribute to the progress in developing antagonists suitable for clinical practice. There are only five venom-derived peptides acting on TRPV1 known up to date.…”

Section: Introductionmentioning

confidence: 99%

Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor

et al. 2016

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Sea anemone venoms comprise multifarious peptides modulating biological targets such as ion channels or receptors. The sequence of a new Kunitz-type peptide, HCRG21, belonging to the Heteractis crispa RG (HCRG) peptide subfamily was deduced on the basis of the gene sequence obtained from the Heteractis crispa cDNA. HCRG21 shares high structural homology with Kunitz-type peptides APHC1–APHC3 from H. crispa, and clusters with the peptides from so named “analgesic cluster” of the HCGS peptide subfamily but forms a separate branch on the NJ-phylogenetic tree. Three unique point substitutions at the N-terminus of the molecule, Arg1, Gly2, and Ser5, distinguish HCRG21 from other peptides of this cluster. The trypsin inhibitory activity of recombinant HCRG21 (rHCRG21) was comparable with the activity of peptides from the same cluster. Inhibition constants for trypsin and α-chymotrypsin were 1.0 × 10−7 and 7.0 × 10−7 M, respectively. Electrophysiological experiments revealed that rHCRG21 inhibits 95% of the capsaicin-induced current through transient receptor potential family member vanilloid 1 (TRPV1) and has a half-maximal inhibitory concentration of 6.9 ± 0.4 μM. Moreover, rHCRG21 is the first full peptide TRPV1 inhibitor, although displaying lower affinity for its receptor in comparison with other known ligands. Macromolecular docking and full atom Molecular Dynamics (MD) simulations of the rHCRG21–TRPV1 complex allow hypothesizing the existence of two feasible, intra- and extracellular, molecular mechanisms of blocking. These data provide valuable insights in the structural and functional relationships and pharmacological potential of bifunctional Kunitz-type peptides.

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“…Indeed this channel family, identified only in Eukaryota, has distinct characteristics with respect the other ones. Specifically, it is a non-selective cation channel gated by a variety of stimuli, such as temperature, pH and ligands binding [76][77][78][79]. In particular these channels have been shown to possess two different gating regions [71,80], which are indeed well-captured by the ED decomposition.…”

Section: Correlation With Dynamical Domainsmentioning

confidence: 99%

From Sequence to Function: Coevolving Amino Acids Encode Structural and Functional Domains

Granata¹,

Ponzoni

Micheletti

et al. 2017

Preprint

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Amino acids interactions within protein families are so optimized that the sole analysis of evolutionary co-mutations can identify pairs of contacting residues. It is also known that evolution conserves functional dynamics, i.e., the concerted motion or displacement of large protein regions or domains. Is it, therefore, possible to use a pure sequence-based analysis to identify these dynamical domains? To address this question, we introduce here a general co-evolutionary coupling analysis strategy and apply it to a curated sequence database of hundreds of protein families. For most families, the sequence-based method partitions amino acids into few clusters. When viewed in the context of the native structure, these clusters have the signature characteristics of viable protein domains: they are spatially separated but individually compact. They have a direct functional bearings too, as shown for various reference cases. We conclude that even large-scale structural and functionally-related properties can be recovered from inference methods applied to evolutionaryrelated sequences. The method introduced here is available as a software package and web server (http://spectrus.sissa.it/spectrus-evo_webserver).

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TRPV1: A Target for Rational Drug Design

Cited by 100 publications

References 158 publications

Breaking barriers to novel analgesic drug development

Breaking barriers to novel analgesic drug development

Kunitz-Type Peptide HCRG21 from the Sea Anemone Heteractis crispa Is a Full Antagonist of the TRPV1 Receptor

From Sequence to Function: Coevolving Amino Acids Encode Structural and Functional Domains

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