Understanding dengue virus capsid protein disordered N-terminal biological activity – playing Lego with proteins to develop peptide inhibitors

Understanding dengue virus capsid protein disordered N-terminal biological activity – playing Lego with proteins to develop peptide inhibitors

Title:
Understanding dengue virus capsid protein disordered N-terminal biological activity – playing
Lego with proteins to develop peptide inhibitors
Authors:
André F. Faustino1, Filomena A. Carvalho1, Fábio Almeida2, Andrea T. Da Poian2, Nuno C.
Santos1, Ivo C. Martins1
1 – Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa,
Portugal;
2 – Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro,
Rio de Janeiro, RJ, 21941-902, Brazil.
Abstract:

Dengue virus (DENV) infection affects millions of people, causing 500,000 hospitalizations
and 20,000 deaths worldwide every year. Dengue is a global disease with epidemics reaching
temperate regions due to globalization of trade and travel and climate change. There are no
therapies. DENV capsid (C) protein interaction with host intracellular lipid droplets (LDs),
crucial for viral replication [1], was characterized by us [2-5]. DENV C binding to lipoproteins,
which may lead to highly infectious lipo-viro particles, was also first reported by us [6, 7].
Studying DENV C-LDs interaction allowed us to design pep14-23, a peptide based on DENV C
N-terminal that inhibits that interaction [1-3]. We originally found that pep14-23 binds
anionic phospholipid membranes acquiring α-helical conformation and an asymmetric charge
distribution and that the DENV C homologous N-terminal transitions between autoinhibitory
α-helical conformations [3]. This plasticity allows DENV C interaction with a greater variety of
biological targets, namely very low-density lipoproteins (VLDL). Interestingly, pep14-23
inhibits DENV C-VLDL binding [7]. We thus investigated the similarity between DENV C
molecular targets in LDs and VLDL, respectively, the proteins perilipin 3 (PLIN3) and
apolipoprotein E (APOE) [5-7]. APOE N-terminal and PLIN3 C-terminal regions, namely APOE
α-helix 4 (APOEα4) and PLIN3 α-helix 5 (PLIN3α5) sequences and structures are quite...

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