The GA-Hecate Peptide inhibits the ZIKV Replicative Cycle in Different Steps and can Inhibit the Flavivirus NS2B-NS3 Protease after Cell Infection

Author(s)

Sanches, Paulo Ricardo da S. ; Faria, Joao Caldana Elias de Campos ; Bittar, Cintia ; Olivieri, Hugo Alexandre Siqueira Guberovich ; Mesquita, Nathalya Cristina de Moraes Roso ; Noske, Gabriela Dias ; de Godoy, Andre Schutzer ; Oliva, Glaucius ; Rahal, Paula ; Cilli, Eduardo Maffud

• Document type: Journal article
• Source: PROTEIN AND PEPTIDE LETTERS; v. 31, n. 7, p. 12-pg., 2024-07-19.

Abstract

Background Peptide drugs are advantageous because they are subject to rational design and exhibit highly diverse structures and broad biological activities. The NS2B-NS3 protein is a particularly promising flavivirus therapeutic target, with extensive research on the development of inhibitors as therapeutic candidates, and was used as a model in this work to determine the mechanism by which GA-Hecate inhibits ZIKV replication.Objective The present study aimed to evaluate the potential of GA-Hecate, a new antiviral developed by our group, against the Brazilian Zika virus and to evaluate the mechanism of action of this compound on the flavivirus NS2B-NS3 protein.Methods Solid-phase peptide Synthesis, High-Performance Liquid Chromatography, and Mass Spectrometry were used to obtain, purify, and characterize the synthesized compound. Real-time and enzymatic assays were used to determine the antiviral potential of GA-Hecate against ZIKV.Results The RT-qPCR results showed that GA-Hecate decreased the number of ZIKV RNA copies in the virucidal, pre-treatment, and post-entry assays, with 5- to 6-fold fewer RNA copies at the higher nontoxic concentration in Vero cells (HNTC: 10 mu M) than in the control cells. Enzymatic and kinetic assays indicated that GA-Hecate acts as a competitive ZIKV NS2B-NS3 protease inhibitor with an IC50 of 32 nM and has activity against the yellow fever virus protease.Conclusion The results highlight the antiviral potential of the GA-Hecate bioconjugate and open the door for the development of new antivirals. (AU)

• FAPESP's process: 22/11644-5 - Antiviral evaluation of peptides conjugated with gallic acid against the virus SARS-CoV-2 using subgenomic replicon
• Grantee: João Caldana Elias de Campos Faria
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 20/05761-3 - Study of the action of synthetic peptides as antivirals against SARS-CoV-2 (COVID-19) and combined evaluation with commercial anti-inflammatories
• Grantee: Eduardo Maffud Cilli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/05411-8 - Development of peptide/guanidine bioconjugates with anti-Leishmania activity
• Grantee: Eduardo Maffud Cilli
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/08342-4 - Development of bioconjugates containing peptides for combined therapy aimed the treatment of Zika and Dengue Virus infection
• Grantee: Paulo Ricardo da Silva Sanches
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/12519-4 - Study of the action of synthetic peptides as antivirals against SARS-CoV-2 (COVID-19) and combined evaluation with commercial anti-inflammatories
• Grantee: Paulo Ricardo da Silva Sanches
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/23244-8 - Development of new peptides and bioconjugates against Zika virus infection
• Grantee: Paulo Ricardo da Silva Sanches
• Support Opportunities: Scholarships in Brazil - Doctorate