This chapter provides a comprehensive up-to-date overview of different types of ARV nanoformulations of drugs, including delivery nanosystems with fixed-dose drug combinations. In this context, it is also necessary to mention the increasing attention paid to HIV preexposure prophylaxis. It is important to note that a number of other natural or inorganic compounds have been shown to be effective against HIV in the nanoform. In addition to oral nanosystems, alternative forms of administration, such as implants, patches, and vaginal preparations, are increasingly being used.
In addition to the design of new drugs and various types of antibodies and vaccines, reformulations of the existing drugs are applied to modern drug delivery nanosystems that enable fixed-dose drug combinations and modified administration, dosing, release, and targeting. On the other hand, during all this time there has been great progress in antiretroviral treatment, which has significantly prolonged and improved the quality of life of HIV-positive patients and AIDS patients. The human immunodeficiency virus (HIV) causing acquired immunodeficiency syndrome (AIDS) in humans appeared about 40 years ago and is still a major global health problem. Viruses can be considered as one of the most common causes of human disease. These scaffolds provide a rich set of starting points for binding a wide range of C2 symmetric compounds. Of these, the geometry of 31 were confirmed by small angle X-ray scattering and 2 were shown by crystallographic analyses to be in close agreement with the computational design models. We used this approach to design thousands of C2 symmetric homodimers, and characterized 101 of them experimentally. We first designed repeat proteins that sample a continuum of curvatures but have low helical rise, then docked these into C2 symmetric homodimers to generate an extensive range of C2 symmetric cavities. Here, we describe a general approach to designing hyperstable C2 symmetric proteins with pockets of diverse size and shape.
For design of binding to symmetric ligands, protein homo-oligomers with matching symmetry are advantageous as each protein subunit can make identical interactions with the ligand. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.įunction follows form in biology, and the binding of small molecules requires proteins with pockets that match the shape of the ligand. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. We first de novo designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies.
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