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Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity

English title Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity
Applicant Hartley Oliver
Number 163085
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Biochemistry
Start/End 01.04.2016 - 31.03.2019
Approved amount 474'000.00
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All Disciplines (5)

Discipline
Biochemistry
Infectious Diseases
Cellular Biology, Cytology
Molecular Biology
Pharmacology, Pharmacy

Keywords (7)

G protein-coupled receptor; G protein coupled receptor kinase; CCR5; arrestin; HIV/AIDS; receptor trafficking; chemokine

Lay Summary (French)

Lead
Grâce à l’ingénierie d'une protéine naturelle nous avons pu générer des puissants inhibiteurs anti-VIH qui pourraient devenir des nouvelles armes contre l’épidémie du VIH/SIDA. Comment fonctionnent ces molécules prometteuses ?
Lay summary

L’épidémie du VIH/SIDA cause actuellement presque 2 millions de nouvelles infections par année, dont la majorité concerne les personnes vivant dans les pays les plus pauvres du monde. Les stratégies de « pre-exposure prophylaxis » – utilisation des produits anti-VIH avant le rapport sexuel afin de se protéger contre l’infection du virus – sont parmi les solutions recherchées en priorité pour combattre l’épidémie.

Certaines protéines de la famille des chimiokines agissent comme des inhibiteurs naturels contre le VIH. En modifiant leur structure nous avons pu améliorer plus que mille fois leur activité anti-virale. Nous préparons actuellement les premiers tests cliniques d’une de ces molécules prometteuses.

Nos chimiokines modifiées agissent via le blocage d’un récepteur humain, le CCR5, qui est également une structure requise par le VIH pour gagner accès aux cellules cibles. Le mécanisme d’inhibition de certaines de nos chimiokines est surprenant. Au lieu de bloquer le CCR5 à la surface de la cellule, elles semblent l’enfermer dans la cellule, hors de portée du virus.

Notre travail actuel pose les questions suivantes : Comment nos molécules modifiées, contrairement aux protéines natives desquelles elles sont dérivées, arrivent ainsi à piéger le récepteur ? Où se trouvent précisément les récepteurs une fois pris au piège ? Par quel chemin y arrivent-ils ?

Direct link to Lay Summary Last update: 22.01.2016

Lay Summary (English)

Lead
Understanding how small modifications to natural human proteins turn them into powerful anti-HIV drugs that could be used to help fight the HIV/AIDS epidemic
Lay summary

The HIV/AIDS epidemic is currently running at over two million new infections per year, most of these occurring in the poorest countries of the world. Among the most promising solutions for combating the epidemic are strategies in which vulnerable people apply anti-HIV drugs before sex to protect themselves against HIV infection.

Certain proteins of the human chemokine family act as natural inhibitors of HIV. By engineering their structure we have improved this anti-viral activity by over thousand-fold. We are currently preparing the first clinical tests of one of these promising molecules as a new medicine to prevent HIV infection.

Our anti-HIV chemokines act via blocking CCR5, a human receptor which is used by HIV to gain access to target cells. The mechanism of inhibition of some of our chemokines is surprising. Instead of blocking the CCR5 at the cell surface, they appear to lock it inside the cell, out of reach of the virus.

This project addresses several questions: Why are our modified molecules, in contrast to native protein from which they are derived, capable of trapping the receiver inside the cell? Where precisely in the cell are the trapped receptors located? And which route do they take to get there?

Answering these questions should help in the development of more effective anti-HIV drugs in the future, as well as providing more general insights into the way cells use receptors to receive and process information from the exterior.

Direct link to Lay Summary Last update: 22.01.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Rapid and low-cost multiplex synthesis of chemokine analogs
Paolini-Bertrand Marianne, Cerini Fabrice, Martins Elsa, Scurci Ilaria, Hartley Oliver (2018), Rapid and low-cost multiplex synthesis of chemokine analogs, in Journal of Biological Chemistry, 293(49), 19092-19100.
CCR5: Established paradigms and new frontiers for a ‘celebrity’ chemokine receptor
Scurci Ilaria, Martins Elsa, Hartley Oliver (2018), CCR5: Established paradigms and new frontiers for a ‘celebrity’ chemokine receptor, in Cytokine, 109, 81-93.
Preventing HIV transmission through blockade of CCR5: rationale, progress and perspectives
HartleyOliver, MartinsElsa, ScurciIlaria (2018), Preventing HIV transmission through blockade of CCR5: rationale, progress and perspectives, in Swiss Medical Weekly, 148(34), w14580.
Stability of 5P12-RANTES, A Candidate Rectal Microbicide, in Human Rectal Lavage
Cerini Fabrice, Offord Robin, McGowan Ian, Hartley Oliver (2017), Stability of 5P12-RANTES, A Candidate Rectal Microbicide, in Human Rectal Lavage, in AIDS Research and Human Retroviruses, 33(8), 768-777.

Collaboration

Group / person Country
Types of collaboration
Case Western Reserve University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Biozentrum Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut Pasteur France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Faculty of Medicine, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of York Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
The Scripps Research Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
The Mintaka Foundation for Medical Research Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration
Rockefeller University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
122594 Studies on inhibition of HIV-1 infection by novel chemokine analogues 01.10.2008 Project funding
131935 Membrane dynamics and conformational diversity of G protein-coupled receptors 01.10.2010 Ambizione
143789 Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity 01.10.2012 Project funding
184828 Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity 01.04.2019 Project funding
184828 Studying the modulation of CCR5 trafficking by chemokine analogues with potent anti-HIV activity 01.04.2019 Project funding

Abstract

CCR5, a chemokine receptor, is the principal coreceptor used by HIV to enter and infect target cells. It is a highly promising target for anti-HIV medicines. For over a decade we have worked on discovering and optimizing analogs of its natural chemokine ligands for use in HIV prevention. We have succeeded in bringing our most promising chemokine analog, 5P12-RANTES, into clinical development, where it is now in a position to play a role in the fight against HIV/AIDS. Of key importance to this project, the set of over 100 chemokine analogs we synthesized and characterized during this effort also represent valuable research tools because they have strikingly novel pharmacological properties and unusual mechanisms of action. This project focuses on using these chemokine analogs to better understand the biology and pharmacology not only of CCR5, but also of the superfamily of seven transmembrane-spanning G protein-coupled receptors (GPCRs) to which it belongs.The GPCR superfamily, which comprises 4% of the coded human genome and provides the targets of 30% of currently licensed medicines, is of great interest to medicine and biology. The convergence of recent advances in structural biology, molecular dynamics and intracellular trafficking has taken the GPCR research field into a phase of rapid evolution. The key feature of this new phase is a deeper appreciation of the conformational flexibility of the receptor and its interaction with three intracellular conformation-sensor proteins: G proteins, arrestins and G protein-coupled receptor kinases (GRKs). New theories have been put forward to explain GPCR activation and desensitization. Robust model systems will now be required to test and extend these theories, and we believe that we are in a position to make a valuable contribution using our system centered on CCR5 and chemokine analogs.In recent work using these analogs, we have (i) demonstrated that CCR5 is subject to unusual intracellular trafficking phenomena, and linked them to the capacity of ligands to elicit CCR5-arrestin association, (ii) found evidence for a previously unobserved mechanism of ligand removal during desensitization, which again appears to be linked to CCR5-arrestin association, and (iii) provided an explanation, based on the association of CCR5 with G proteins, for the observation that CCR5 exists in antigenically distinct forms at the cell surface. We have also set up and validated bioluminescence resonance energy transfer-based methods, which will greatly facilitate the quantification of interaction between CCR5 and its intracellular conformation-sensor proteins in real time and in living cells.We now seek to build on this progress, measuring recruitment and activation of the key conformation-sensor proteins in order to interpret how modifications in CCR5 ligand structure generate different signaling and trafficking outcomes in the cell. We will pay particularly close attention to the relatively unexplored role of GRKs. Using CCR5 and our chemokine analogs as a model system in this way, we hope to be able to contribute to the generation of a fully integrated molecular and cellular explanation of GPCR activation. Generating such an explanation would have a transformative effect not only on understanding of GPCR biology but also in GPCR-targeted drug discovery, where it may be possible for the first time to rationally design ligands that modulate the receptors to achieve a specific pharmacological outcome.
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