A Precise Chemical Strategy To Alter the Receptor Specificity of the Adeno-Associated Virus

The ability to target the adeno‐associated virus (AAV) to specific types of cells, by altering the cell‐surface receptor it binds, is desirable to generate safe and efficient therapeutic vectors. Chemical attachment of receptor‐targeting agents onto the AAV capsid holds potential to alter its tropism, but is limited by the lack of site specificity of available conjugation strategies. The development of an AAV production platform is reported that enables incorporation of unnatural amino acids (UAAs) into specific sites on the virus capsid. Incorporation of an azido‐UAA enabled site‐specific attachment of a cyclic‐RGD peptide onto the capsid, retargeting the virus to the αvβ3 integrin receptors, which are overexpressed in tumor vasculature. Retargeting ability was site‐dependent, underscoring the importance of achieving site‐selective capsid modification. This work provides a general chemical approach to introduce various receptor binding agents onto the AAV capsid with site selectivity to generate optimized vectors with engineered infectivity. Eine Produktionsplattform für Adeno‐assoziierte Viren (AAVs) ermöglicht den effizienten Einbau nichtnatürlicher Aminosäuren an bestimmten Positionen des Viruskapsids. Damit steht ein chemischer Ansatz zur Verfügung, um verschiedene Rezeptor‐bindende Agentien ortsselektiv in das AAV‐Kapsid einzuführen und optimierte Vektoren mit gezielt entworfener Infektiosität zu erzeugen.