Semaglutide is the active ingredient in Wegovy, Ozempic, and Rybelsus. Semaglutide is a pharmaceutical substance used for weight loss and to lower blood sugar levels and reduce the risk of serious cardiovascular complications such as heart attack or stroke in patients with type $2$ diabetes.

a$)$ Semaglutide is a glucagon$-$like$-$peptide$-1($GLP$-1)$ receptor agonist that is structurally very similar to the GLP$-1$ peptide. A crucial modification is that the side chain of lysine $($amino acid number $20)$ is conjugated via a linker $($bis$-$aminodietoxyacetyl$)$ to a fatty acid $($a dicarboxylic fatty acid with $18$ carbons$).$ The attached fatty acid part is essential for significantly prolonging the half$-$life of the GLP$-1$ agonist. The reason for the extended half$-$life is that the fatty acid part makes the molecule bind strongly but reversibly to serum albumin, which protects the peptide from degradation. Which $2$ central intermolecular forces are likely to be involved in the binding to serum albumin? Explain briefly.

b$)$ In addition to the attached fatty acid part, another modification was made to the structure to improve the properties of the GLP$-1$ agonist: amino acid number $2$ from the N$-$terminus was changed from an alanine to a $2-$aminoisobutyric acid. This prevents degradation by the enzyme dipeptidyl peptidase IV $($DPP$-$IV$).$ Explain how you believe the change protects against DPP IV$-$mediated degradation. Also, provide examples of $2$ other general strategies that can be used in drug design to extend half$-$lives.

c$)$ What administration route is likely for semaglutide based on its structure? Explain your reasoning!

d$)$ Other drugs used in the treatment of diabetes are DPP$-$IV inhibitors such as saxagliptin; see the structure below. Saxagliptin is administered as a hydrochloride salt. Draw the hydrochloride salt of saxagliptin and show with a simple mechanism how saxagliptin reacts with HCl$.$ You should draw here it's not enough to just explain with words!!

e$)$ In drug development, it is common to make structural variations based on bioisosterism. Propose $2$ new analogs of saxagliptin with likely retained efficacy using different types of bioisosterism. Draw and justify your proposals. YOU SHOULD DRAW here!!