Feline Immunodeficiency Virus Plasma Load Reduction by a Retroinverso Octapeptide Reproducing the Trp-Rich Motif of the Transmembrane Glycoprotein

Giannecchini, Simone; Alcaro, Maria C.; Isola, Patrizia; Sichi, Olimpia; Pistello, Mauro; Papini, Anna Maria; Rovero, Paolo; Bendinelli, Mauro

doi:10.1177/135965350501000505

Cited by 14 publications

(2 citation statements)

References 45 publications

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“…The MPER has been reported to be an exposed region harboring epitopes for broadly neutralizing antibodies and regarded as a desirable target for antiviral therapeutics for its accessibility and sequential conservation. − Indeed, the inclusion of MPER sequences has been proven to be essential for both first- and second-generation fusion inhibitors against HIV-1. Similarly, an octapeptide derived from the FIV MPER has been shown to act as a mild entry inhibitor. , In virus inhibition assays, both peptides derived from IBV M-ibv and SARS-CoV M-wt inhibited IBV-Luc entry and infection. M-3W3A totally loses its virus neutralization ability.…”

Section: Discussionmentioning

confidence: 99%

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Tryptophan-Dependent Membrane Interaction and Heteromerization with the Internal Fusion Peptide by the Membrane Proximal External Region of SARS-CoV Spike Protein

et al. 2015

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The spike (S) protein of severe acute respiratory syndrome-associated CoV (SARS-CoV) mediates membrane fusion and viral entry. These events involve structural rearrangements, including heteromerization between two heptad repeats (HR1 and HR2) to form a trimer of dimers as a six-helix bundle (6-HB), a quaternary protein structure that brings two distant clusters of hydrophobic sequences into the proximity of each other, the internal fusion peptide (IFP) preceding HR1, and the highly conserved tryptophan (Trp)-rich membrane proximal external region (MPER) following HR2. Here, we show that MPER can undergo self-oligomerization and heteromerization with IFP, events that are Trp-dependent. To delineate the roles of Trp residues of MPER in forming these quaternary structures and interacting with membranes, we employed a panel of synthetic peptides: MPER peptide (M-wt) and its alanine (Ala) and phenylalanine (Phe) analogues. Ala substitutions of Trp inhibited its association with cellular membranes. Chemical cross-linking experiments showed that M-wt can self-interact to form oligomers and cross-interact with IFP23, a synthetic IFP peptide, to form a heterohexamer. In comparison, little high-order oligomer was formed between M-wt and fusion peptide. The specific interaction between M-wt and IFP23 was confirmed by immunofluorescence staining experiments. In aqueous solutions, both M-wt and IFP23 displayed random secondary structures that became helical in hydrophobic solvents. Triple-Ala substitutions of Trp in M-wt, but not the corresponding triple-Phe analogue, disrupted oligomerization of M-wt and hetero-oligomerization of M-wt with IFP23. Overall, our results show that Trp residues of MPER play a key role in maintaining the structure and functions of MPER, allowing it to interact with IFP to form a MPER-IFP heteromer, a putative quaternary structure extending from the 6-HB, and function in membrane fusion. Finally, we showed that a MPER peptide could serve as an inhibitor in the entry process.

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Section: Discussionmentioning

confidence: 99%

“…Similarly, an octapeptide derived from the FIV MPER has been shown to act as a mild entry inhibitor. 52,53 In virus inhibition assays, both peptides derived from IBV M-ibv and SARS-CoV M-wt inhibited IBV-Luc entry and infection. M-3W3A totally loses its virus neutralization ability.…”

Section: ■ Discussionmentioning

confidence: 99%

Tryptophan-Dependent Membrane Interaction and Heteromerization with the Internal Fusion Peptide by the Membrane Proximal External Region of SARS-CoV Spike Protein

et al. 2015

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Development of Antiviral Fusion Inhibitors: Short Modified Peptides Derived from the Transmembrane Glycoprotein of Feline Immunodeficiency Virus

et al. 2006

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Feline immunodeficiency virus (FIV) is a naturally occurring pathogen that causes an AIDS-like syndrome in domestic cats and is a valuable model system by which criteria for antiviral vaccines and drugs development can be tested. The cell-entry step of the lentivirus life cycle is regarded as a promising target for the development of new generation inhibitors. We have previously described potent in vitro anti-FIV activity associated with a synthetic octapeptide, termed C8 (Ac-Trp-Glu-Asp-Trp-Val-Gly-Trp-Ile-NH2), containing the Trp-rich motif of FIV transmembrane glycoprotein, which shares a common structural framework with the corresponding molecule of HIV and appears to play a similar role in cell entry. In this report, in an attempt to develop simpler potential fusion inhibitors to be tested in vivo, we describe further studies focused on synthetic peptide analogues of C8. Since C8 inhibitory activity is dependent upon the Trp motif, we systematically replaced these residues with bulky and/or aromatic natural and unnatural amino acids, in order to develop a rational structure-activity relationship. Furthermore, the amino acids located between the Trp residues, which are not crucial for inhibitory activity, were replaced by simple alkyl spacers of appropriate length. Design, NMR structural analysis, in vitro anti-FIV activity in lymphoid cell cultures, and serum stability of these new analogues are reported. The final results indicate that a simpler hexapeptide (Ac-Nal2-Ape-Nal2-Ape-Nal2-Ile-NH2; Nal2 = 3-naphthalen-2-yl-L-alanine, Ape = 5-aminopentanoic acid), almost entirely made up of unnatural amino acid residues, has markedly increased enzymatic stability, while maintaining strong antiviral potency in vitro.

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Interfacial pre-transmembrane domains in viral proteins promoting membrane fusion and fission

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Huarte

Sáez‐Cirión

et al. 2008

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Membrane fusion and fission underlie two limiting steps of enveloped virus replication cycle: access to the interior of the host-cell (entry) and dissemination of viral progeny after replication (budding), respectively. These dynamic processes proceed mediated by specialized proteins that disrupt and bend the lipid bilayer organization transiently and locally. We introduced Wimley-White membrane-water partitioning free energies of the amino acids as an algorithm for predicting functional domains that may transmit protein conformational energy into membranes. It was found that many viral products possess unusually extended, aromatic-rich pre-transmembrane stretches predicted to stably reside at the membrane interface. Here, we review structure-function studies, as well as data reported on the interaction of representative peptides with model membranes, all of which sustain a functional role for these domains in viral fusion and fission. Since pre-transmembrane sequences also constitute antigenic determinants in a membrane-bound state, we also describe some recent results on their recognition and blocking at membrane interface by neutralizing antibodies.

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Feline Immunodeficiency Virus Plasma Load Reduction by a Retroinverso Octapeptide Reproducing the Trp-Rich Motif of the Transmembrane Glycoprotein

Cited by 14 publications

References 45 publications

Tryptophan-Dependent Membrane Interaction and Heteromerization with the Internal Fusion Peptide by the Membrane Proximal External Region of SARS-CoV Spike Protein

Tryptophan-Dependent Membrane Interaction and Heteromerization with the Internal Fusion Peptide by the Membrane Proximal External Region of SARS-CoV Spike Protein

Development of Antiviral Fusion Inhibitors: Short Modified Peptides Derived from the Transmembrane Glycoprotein of Feline Immunodeficiency Virus

Interfacial pre-transmembrane domains in viral proteins promoting membrane fusion and fission

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