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Exploring protein-protein interactions for the development of new analgesics.
do Nascimento, Alexandre Martins; Marques, Rauni Borges; Roldão, Allan Pradelli; Rodrigues, Ana Maria; Eslava, Rodrigo Mendes; Dale, Camila Squarzoni; Reis, Eduardo Moraes; Schechtman, Deborah.
Afiliação
  • do Nascimento AM; Department of Biochemistry, Chemistry Institute, University of São Paulo, SP 05508-000, Brazil.
  • Marques RB; Laboratory of Neuromodulation of Experimental Pain (LaNed), Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, SP 05508-000, Brazil.
  • Roldão AP; Department of Biochemistry, Chemistry Institute, University of São Paulo, SP 05508-000, Brazil.
  • Rodrigues AM; Interunit Graduate Program in Bioinformatics, University of São Paulo, SP 05508-000, Brazil.
  • Eslava RM; Department of Biochemistry, Chemistry Institute, University of São Paulo, SP 05508-000, Brazil.
  • Dale CS; Department of Biochemistry, Chemistry Institute, University of São Paulo, SP 05508-000, Brazil.
  • Reis EM; Department of Biochemistry, Chemistry Institute, University of São Paulo, SP 05508-000, Brazil.
  • Schechtman D; Laboratory of Neuromodulation of Experimental Pain (LaNed), Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, SP 05508-000, Brazil.
Sci Signal ; 17(857): eadn4694, 2024 10 08.
Article em En | MEDLINE | ID: mdl-39378285
ABSTRACT
The development of new analgesics has been challenging. Candidate drugs often have limited clinical utility due to side effects that arise because many drug targets are involved in signaling pathways other than pain transduction. Here, we explored the potential of targeting protein-protein interactions (PPIs) that mediate pain signaling as an approach to developing drugs to treat chronic pain. We reviewed the approaches used to identify small molecules and peptide modulators of PPIs and their ability to decrease pain-like behaviors in rodent animal models. We analyzed data from rodent and human sensory nerve tissues to build associated signaling networks and assessed both validated and potential interactions and the structures of the interacting domains that could inform the design of synthetic peptides and small molecules. This resource identifies PPIs that could be explored for the development of new analgesics, particularly between scaffolding proteins and receptors for various growth factors and neurotransmitters, as well as ion channels and other enzymes. Targeting the adaptor function of CBL by blocking interactions between its proline-rich carboxyl-terminal domain and its SH3-domain-containing protein partners, such as GRB2, could disrupt endosomal signaling induced by pain-associated growth factors. This approach would leave intact its E3-ligase functions, which are mediated by other domains and are critical for other cellular functions. This potential of PPI modulators to be more selective may mitigate side effects and improve the clinical management of pain.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Analgésicos Limite: Animals / Humans Idioma: En Revista: Sci Signal Assunto da revista: CIENCIA / FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Analgésicos Limite: Animals / Humans Idioma: En Revista: Sci Signal Assunto da revista: CIENCIA / FISIOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Brasil País de publicação: Estados Unidos