Periodic Reporting for period 1 - Super-HIPPO (Development of artificial phosphoinositides aiming at HIV eradication)
Período documentado: 2023-09-01 hasta 2025-10-31
Despite major advances in antiretroviral therapy, HIV remains incurable due to the persistence of latent viral reservoirs that evade immune clearance and reignite infection if treatment is stopped. Current eradication strategies, such as the widely explored “kick and kill” approach, have shown limited success because reactivated infected cells are not efficiently eliminated. There is therefore a critical unmet need for innovative therapeutic concepts that prevent viral rebound and selectively eliminate infected cells.
The Super-HIPPO project addresses this challenge by developing a fundamentally new strategy termed “lock-in and apoptosis.” Instead of reactivating latent virus, this approach blocks HIV assembly at the host cell membrane and simultaneously triggers programmed cell death in infected cells. The strategy targets the matrix (MA) domain of the HIV-1 Gag polyprotein, a key component required for viral particle formation through its interaction with host cell phosphoinositides.
Building on earlier proof-of-concept studies, the project aimed to design and optimize a novel artificial phosphoinositide derivative (Super-HIPPO) with enhanced biological activity and improved intracellular delivery. The overarching objective was to generate a new class of anti-HIV agents capable of suppressing virus production and promoting selective apoptosis of infected cells, thereby contributing to long-term HIV eradication efforts.
At a broader level, the project supports EU priorities in global health, innovation in antiviral therapies, and preparedness against persistent and emerging infectious diseases. By combining medicinal chemistry, nanotechnology, molecular Biology, and structural biology, Super-HIPPO establishes a scalable pathway toward transformative HIV therapies with potential impact well beyond the lifetime of the project.
The Super-HIPPO project addresses this challenge by developing a fundamentally new strategy termed “lock-in and apoptosis.” Instead of reactivating latent virus, this approach blocks HIV assembly at the host cell membrane and simultaneously triggers programmed cell death in infected cells. The strategy targets the matrix (MA) domain of the HIV-1 Gag polyprotein, a key component required for viral particle formation through its interaction with host cell phosphoinositides.
Building on earlier proof-of-concept studies, the project aimed to design and optimize a novel artificial phosphoinositide derivative (Super-HIPPO) with enhanced biological activity and improved intracellular delivery. The overarching objective was to generate a new class of anti-HIV agents capable of suppressing virus production and promoting selective apoptosis of infected cells, thereby contributing to long-term HIV eradication efforts.
At a broader level, the project supports EU priorities in global health, innovation in antiviral therapies, and preparedness against persistent and emerging infectious diseases. By combining medicinal chemistry, nanotechnology, molecular Biology, and structural biology, Super-HIPPO establishes a scalable pathway toward transformative HIV therapies with potential impact well beyond the lifetime of the project.
The project successfully integrated chemical synthesis, nanocarrier development, biological evaluation, and structural studies. A novel inositol-based phosphoinositide derivative was designed and synthesized through an optimized synthetic route. Its chemical structure and purity were confirmed using advanced spectroscopic techniques. To overcome poor membrane permeability associated with highly charged phosphates, biocompatible magnetic nanocarriers based on iron oxide were developed and functionalized to deliver the compound efficiently into HIV-infected cells. Comprehensive in vitro studies demonstrated that the nanocarrier-delivered compound binds strongly to the HIV-1 MA protein and disrupts Gag localization at the plasma membrane. As a result, viral particle release was markedly reduced. Importantly, treatment led to a strong induction of apoptosis in infected cells, validating the “lock-in and apoptosis” concept.
In parallel, large-scale production and purification of HIV-1 MA protein enabled extensive crystallization trials. Numerous MA-compound co-crystals were obtained, and diffraction data were collected using a newly established home-source X-ray facility. Although structural resolution was limited, these efforts provided valuable insights into protein-ligand interactions and established advanced structural biology infrastructure.
Overall, the project met its core scientific objectives and generated robust experimental evidence supporting a new antiviral mechanism of action.
In parallel, large-scale production and purification of HIV-1 MA protein enabled extensive crystallization trials. Numerous MA-compound co-crystals were obtained, and diffraction data were collected using a newly established home-source X-ray facility. Although structural resolution was limited, these efforts provided valuable insights into protein-ligand interactions and established advanced structural biology infrastructure.
Overall, the project met its core scientific objectives and generated robust experimental evidence supporting a new antiviral mechanism of action.
Super-HIPPO delivers results that go beyond current HIV therapeutic paradigms by introducing a non-reactivating eradication strategy that combines viral assembly inhibition with selective apoptosis induction. This dual mechanism represents a significant conceptual advance over existing approaches that rely solely on viral suppression or immune-mediated clearance.
The artificial phosphoinositide developed in this project constitutes a new molecular scaffold targeting HIV assembly rather than viral enzymes, opening opportunities for therapies less prone to classical drug resistance. The successful use of nanocarriers further demonstrates a viable route for delivering highly charged antiviral compounds intracellularly.
For further uptake and translation, key next steps include advanced preclinical studies, optimization of delivery systems for in vivo use, and exploration of scalable manufacturing routes. Intellectual property protection, regulatory alignment, and partnerships with pharmaceutical and biotechnology stakeholders will be essential to support clinical development and commercialization.
Beyond HIV, the conceptual framework and delivery technologies established here may be adaptable to other viral infections that rely on host membrane interactions, amplifying the long-term scientific and societal impact.
The artificial phosphoinositide developed in this project constitutes a new molecular scaffold targeting HIV assembly rather than viral enzymes, opening opportunities for therapies less prone to classical drug resistance. The successful use of nanocarriers further demonstrates a viable route for delivering highly charged antiviral compounds intracellularly.
For further uptake and translation, key next steps include advanced preclinical studies, optimization of delivery systems for in vivo use, and exploration of scalable manufacturing routes. Intellectual property protection, regulatory alignment, and partnerships with pharmaceutical and biotechnology stakeholders will be essential to support clinical development and commercialization.
Beyond HIV, the conceptual framework and delivery technologies established here may be adaptable to other viral infections that rely on host membrane interactions, amplifying the long-term scientific and societal impact.