RESUMO
Mechanisms of infection are deciphered at the host-pathogen interface.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Endossomos , Neuropilina-1 , Receptores Virais , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Endossomos/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Neuropilina-1/antagonistas & inibidores , Receptores Virais/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Rede trans-Golgi/virologia , Internalização do Vírus/efeitos dos fármacos , HumanosRESUMO
The COVID-19 pandemic continues without specific treatment. In this study it is proposed compounds that can be developed as adjuvant / complementary drugs against COVID-19. Through a search for molecular docking, for the development of a new drug using pharmacological compounds targeting the b1 region in neuropilin-1 (NRP1), which is important for the interaction with the S1 region of the S-Protein of SARS-CoV-2, to slow down the infection process of this virus. A molecular docking was performed using almost 500,000 compounds targeted to interact in the region between amino acids (Thr316, Asp320, Ser346, Thr349, and Tyr353) in NRP1 to determine compounds able to hinder the interaction with the S1 region in the S-Protein. In this study, ten compounds are proposed as potential inhibitors between S1 region in the S-Protein of SARS-CoV-2 with the b1 region in NRP1, to develop a new adjuvant / complementary drug against COVID-19, and to hinder the interaction between SARS-CoV-2 and human cells, with a high probability to be safe in humans, validated by web servers for prediction of ADME and toxicity (PreADMET).
Assuntos
Simulação de Acoplamento Molecular , Neuropilina-1/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Antivirais/química , Antivirais/metabolismo , Antivirais/uso terapêutico , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Reposicionamento de Medicamentos , Humanos , Neuropilina-1/metabolismo , SARS-CoV-2/isolamento & purificação , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1. Blocking this interaction by RNA interference or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19.