Home » Key Drug Discovery Articles » Definition of an 18-mer Synthetic Peptide Derived from the GB virus C E1 Protein as a New HIV-1 Entry Inhibitor

Definition of an 18-mer Synthetic Peptide Derived from the GB virus C E1 Protein as a New HIV-1 Entry Inhibitor

Significance Statement

In this article we report the construction of several peptide libraries scanning the GB virus C (GBV-C) E1 protein and the evaluation of their anti-HIV-1 activity. On the basis of the results, an 18-mer synthetic peptide, specifically the sequence E1(139-156) (namely E1P47), is defined as a new anti-HIV-1 peptide entry inhibitor. The peptide showed similar antiviral activity against viruses from clades A, B, C, D and AE. The broad spectrum of activity against HIV-1 that E1P47 has been demonstrated to have, as well as its capacity to prevent HIV infection by inhibiting (at least partially) viral entry, constitute favourable properties when evaluating this small peptide as a microbicide lead. We consider that these results are of interest for people working in the field of discovering new peptides with the ability of inhibiting HIV and more specifically those involved in studying the relationship of GB virus C and HIV viruses. The results described in the present work indicate the implication of the E1 envelope of the GB virus C in the inhibition of HIV-1. Moreover, our results also highlight the definition of one inhibiting domain within this protein. Thus, taken together the results allow us to consider also the non-pathogenic E1 GB virus C protein as an attractive source of peptides for the development of novel anti-HIV therapies. We strongly believe that the results reported here are important in themselves, so far as we have defined a novel lead compound as in that for the first time the inhibitory role of a highly conserved fragment of the E1 protein is reported.

Group information

The research interests of the Unit of Synthesis and Biomedical Applications of Peptides deal with the use of peptides for the development of new biosensors for the diagnosis of human illnesses and on the selection of therapeutic agents of peptide origin through biophysical testing.

Specifically, in the field of synthetic peptides for the diagnosis and prognosis of rheumatoid arthritis, we aim to identify new antigen peptides, derived from citrullinated/homocitrullinated proteins present in rheumatoid synovial fluid (fibrin, filaggrin, vimentin and enolase) in order to thereby identify those patients who require more aggressive therapies right from the moment of diagnosis of the disease. That would allow greater control of the disease and, consequently, less harm to the articulations and a better prognosis. Moreover, the detection of a single biomarker is not always sufficiently sensitive or precise to discriminate between RA patients with different prognoses, clinical characteristics or responses to therapy. Through the simultaneous analysis of the target peptides, incorporated into a multiplex test, we aim to facilitate the biological fingerprinting of autoantibodies in serum that will be able to identify subgroups of patients with specific clinical characteristics; different prognoses; and who either respond well to, or suffer negative effects from, certain therapeutic interventions. These results could have far-reaching practical implications for establishing the most appropriate therapeutic strategy for RA patients.

Related with the study of peptide human immunodeficiency virus entry inhibitors, we propose the study of new therapeutic agents for the treatment of AIDS, together with the development of a biosensor platform that can be used to detect antibodies against GB virus C in patients co-infected with HIV-1.

Finally, the objective of the research line on peptide controlled-release nanosystems for ocular administration of drugs includes the development of new systems of administration based on liposomes and nanoparticles that are targeted via the use of peptides and that can ensure low levels of irritation, sufficient bioavailability and compatibility with ocular tissues.

GB virus C E1 Protein as a New HIV-1 Entry Inhibitor. Global Medical Discovery

About The Author

Prof. Isabel Haro. Senior Staff. B.Sc. Chemistry, University of Barcelona, 1982. M.Sc. Biochemistry,University of Barcelona, 1984. Ph.D. Chemistry, University of Barcelona, 1988. Postdoctoral fellow (1989-1990) between CSIC in Barcelona and Royal Free Hospital in London (Prof. G. Gregoriadis). Research Scientist at CSIC leading the Unit of Synthesis and Biomedical Applications of CSIC in 1990. Since then she has been working in the use of synthetic peptides in the field of biomedicine, specifically in the development of new biosensors for the diagnosis of human illnesses and in the selection of new therapeutic agents of peptide origin through biophysical testing. She has published more than 180 articles, 8 reviews, 30 chapters of books and 8 patents. Also, she has been the principal researcher of 15 research projects and 3 contracts with the industry and supervised 12 doctoral theses. e-mail contact: [email protected]

About The Author

Dr. Maria JoséGomara. Senior Staff. B.Sc. Pharmacy, University of Barcelona, 1992. M.Sc. Physical Chemistry, University of Barcelona, 1995. Ph.D. Pharmacy, University of Barcelona, 2000. Postdoctoral fellow (2001-2004) in Prof. Felix Goñi laboratory (Biophysical Unit, CSICEHU/UPV). Research assistant (2005-2007) in the Unit of Synthesis and Biomedical Applications of Peptides leaded by Dr. Haro, IQAC-CSIC. Research scientist of CSIC since 2008. Experience in peptide synthesis, biophysical studies of peptide-lipid and peptide-peptide interactions and development of peptide-based immunoassays. She has published over 60 articles and 5 patents. e-mail contact: [email protected]

Journal Reference

Gómara MJ1, Sánchez-Merino V2, Paús A3, Merino-Mansilla A2, Gatell JM4, Yuste E2, Haro I5.
Show Affiliations
  1. Unit of Synthesis and Biomedical Application of Peptides. IQAC-CSIC, Jordi Girona, 18-26, 08034 Barcelona, Spain. Electronic address: [email protected]
  2. AIDS Research Unit, Institut d’Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. HIVACAT, Barcelona, Spain.
  3. Unit of Synthesis and Biomedical Application of Peptides. IQAC-CSIC, Jordi Girona, 18-26, 08034 Barcelona, Spain.
  4. AIDS Research Unit, Institut d’Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain. HIVACAT, Barcelona, Spain; Infectious Diseases Unit-HIVACAT, Hospital Clinic, Villarroel, 170, 08036 Barcelona, Spain.
  5. Unit of Synthesis and Biomedical Application of Peptides. IQAC-CSIC, Jordi Girona, 18-26, 08034 Barcelona, Spain. Electronic address: [email protected]

Abstract

BACKGROUND:

A slower progression of AIDS and increased survival in GB virus C positive individuals, compared with GB virus C negative individuals has been demonstrated; while the loss of GB virus C viremia was closely associated with a rise in mortality and increased progression of AIDS. Following on from the previous reported studies that support the thesis that GB virus C E2 interferes with HIV-1 entry, in this work we try to determine the role of the GB virus C E1 protein in HIV-1 inhibition.

METHODS:

The present work involves the construction of several overlapping peptide libraries scanning the GBV-C E1 protein and the evaluation of their anti-HIV activity.

RESULTS:

Specifically, an 18-mer synthetic peptide from the GB virus C E1 protein, E1(139-156), showed similar antiviral activity against HIVs from viruses from clades A, B, C, D and AE. Competitive ELISA using specific gp41-targeting mAbs, fluorescence resonance energy transfer as well as haemolysis assays demonstrated that this E1 peptide sequence interacts with the highly conserved N-terminal region of the HIV-1 gp41 (the fusionpeptide) which is essential for viral entry.

CONCLUSIONS:

We have defined a novel peptide lead compound and described the inhibitory role of a highly conserved fragment of the E1 protein.

GENERAL SIGNIFICANCE:

The results together allow us to consider the non-pathogenic E1 GB virus C protein as an attractive source of peptides for the development of novel anti-HIV therapies.

Copyright © 2016 Elsevier B.V. All rights reserved.

Go To Biochim Biophys Acta