Abstract
Globally 38 million people were living with the human immunodeficiency virus (HIV) in 2019 with 1.7 million new infections. Infection rates have declined, with a drop of 23% since 2010 due to the greater availability of both testing and treatment. There still remains no cure for the disease, therefore anyone who contracts HIV must begin anti-retroviral therapy (ART), which will require a daily administration for the entirety of the person’s life. These medications work to slow or even stop the progression of the disease, but they also come with severe side effects and viral resistance. The focus has turned to ways of preventing the spread before it is able to infect new hosts. Currently, pre-exposure prophylaxis (PrEP), is available to those who are at higher risk of contracting the disease. These medications have shown promise, but still carry much of the same issues experienced with the medications from ART. Focusing on the preventative measures as a way to fight the spread of the virus is the focus of the current study. For the current project, an optimization for the synthesis of a sulfated glycodendrimer was achieved through the synthesis of eighteen unique compounds. Optimization of the linker synthesis was achieved through eliminating halting via acidification of the reaction and instead going straight to purification by flash chromatography. By contrast the tetra-nitrile core yields were increased through pH adjustments during the extraction process, eliminating the need for flash chromatography. The synthesis of the tetra-amine core was optimized through removing both the magnesium hydroxide and methanol, which allowed the 1,3-diaminopropane to act as the solvent, catalyst and reactant. This led to a greener reaction step and higher overall yields. The glycosylation reactions were shown to be efficient with this core, and for each of the sugars resulted in yields from the mid to high 90%’s. The sulfation reactions worked well with the lower-level saccharide chain lengths of the monomer and dimer glycodendrimers with their percent sulfur being 16.10% (w/v) and 11.60% (w/v), respectively. However, when it came to the larger oligosaccharide chain lengths of the trimer and tetramer glycodendrimers, the percent sulfation dropped to 3.73% and 1.94%, respectively. These larger oligosaccharides were shown to have a higher impact on the ability sulfate more than one site per arm. These reactions will require further investigation through longer reaction times and temperature variations to increase the sulfation amount. The sulfogylcodendrimers (SGDs) produced in this study are now ready for biological testing with the gp120 spike protein as well as the SARS-CoV-2 viral spike protein. The SGDs will be analyzed for their binding ability to these surface proteins to examine their efficacy for inhibiting the viruses. These compounds will be sent out to out collaborators at Duke University where they will undergo both an inhibition of infectivity assay as well as cytotoxicity testing. These two tests will test the ability of the compounds to inhibit HIV while also exhibiting no toxicity against human cells. This study has resulted in the successful synthesis of four octavalent sulfoglycodendrimers of varying oligosaccharide lengths. Following the biological testing of these products, they may be incorporated into various preventative measures against STI contraction through implementation in topical creams.