Phospholipase A2 isolated from the venom of Crotalus durissus terrificus inactivates dengue virus and other enveloped viruses by disrupting the viral envelope.
The Flaviviridae family includes several virus pathogens associated with human diseases worldwide. Within this family, Dengue virus is the most serious threat to public health, especially in tropical and sub-tropical regions of the world. Currently, there are no vaccines or specific antiviral drugs against Dengue virus or against most of the viruses of this family. Therefore, the development of vaccines and the discovery of therapeutic compounds against the medically most important flaviviruses remain a global public health priority. We previously showed that phospholipase A2 isolated from the venom of Crotalus durissus terrificus was able to inhibit Dengue virus and Yellow fever virus infection in Vero cells. Here, we present evidence that phospholipase A2 has a direct effect on Dengue virus particles, inducing a partial exposure of genomic RNA, which strongly suggests inhibition via the cleavage of glycerophospholipids at the virus lipid bilayer envelope. This cleavage might induce a disruption of the lipid bilayer that causes a destabilization of the E proteins on the virus surface, resulting in inactivation. We show by computational analysis that phospholipase A2 might gain access to the Dengue virus lipid bilayer through the pores found on each of the twenty 3-fold vertices of the E protein shell on the virus surface. In addition, phospholipase A2 is able to inactivate other enveloped viruses, highlighting its potential as a natural product lead for developing broad-spectrum antiviral drugs.
Laboratório de Virologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Vanessa Danielle
VD
Muller
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Ricardo Oliveira
RO
Soares
Laboratório de Virologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Nilton Nascimento
NN
dos Santos
Laboratório de Virologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Amanda Cristina
AC
Trabuco
Laboratório de Toxinologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Adelia Cristina
AC
Cintra
Centro de Pesquisa em Virologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Luiz Tadeu
LT
Figueiredo
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Antonio
A
Caliri
Laboratório de Toxinologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Suely Vilela
SV
Sampaio
Laboratório de Virologia, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brasil.
Victor Hugo
VH
Aquino
D000818:Animals; D000998:Antiviral Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003435:Crotalid Venoms / Q000201:enzymology*; D017839:Crotalus; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology*; D008051:Lipid Bilayers / Q000378:metabolism; D054467:Phospholipases A2 / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D014709:Vero Cells; D014771:Virion / Q000187:drug effects / Q000502:physiology; D038301:Virus Inactivation / Q000187:drug effects*
D000998:Antiviral Agents; D003435:Crotalid Venoms; D008051:Lipid Bilayers; D054467:Phospholipases A2