BICEPSvsHIV · Novel strategies for anti-HIV-1 therapy: Small molecules targeting RNA partners of the nucleocapsid protein

Novel strategies for anti-HIV-1 therapy: Small molecules targeting RNA partners of the nucleocapsid protein

Human Immunodeficiency Virus (HIV) infection remains of major public health importance. Most of the commonly available drugs, although potent and selective, experienced clinical failures and severe side effects. Alternative antiretroviral drugs and novel therapeutic strategies are thus urgently needed to overcome the emergence of resistance to existing drugs. The project “BICEPSvsHIV” proposed a new anti-HIV strategy focused on RNA. Specific RNA sequences of the viral genome are substrates of proteins, such as the HIV-1 nucleocapsid (NC), a highly conserved protein known for promoting remodeling of nucleic acid structures acting in essential steps of the virus replication cycle. Our working hypothesis was that the employment of bis-3-chloropiperidines (BICEPS) as RNA targeting agents could represent a novel pharmacological treatment to impair NC-mediated processes, while overcoming drug resistance. Small molecules able to bind to the RNA substrates of NC and freeze their three-dimensional configurations were already shown to block NC-mediated remodelling of nucleic acids secondary structures. The Experienced Researcher (ER) worked at The RNA Institute (SUNY Albany, NY, USA) in the research laboratory of Prof. Dan Fabris during the outgoing phase, whereas she performed her research at the Department of Pharmaceutical and Pharmacological Sciences (University of Padova, Padova, Italy) in the research laboratory of Prof. Barbara Gatto during the incoming phase. During these two years, all the proposed research objectives of the project were met. The conclusions of the action are: 1) we identified positive hits targeting selectively the RNA substrates of NC, with different reactivity and selectivity, and we described their detailed molecular mechanism of reactions towards RNA, including the fast and specific cross-linking of different RNA structures; 2) in the in vitro biological analysis, we established how the exquisite reactivity with RNA led to the stabilization of their dynamical conformation leading to the inhibition of NC-mediated remodelling of the nucleic acids structures; 3) we established the structure-activity relationships of BICEPS, useful to optimize RNA specific cross-linking agents for the development of anti-NC lead compounds.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз