**2.5 Membrane transporters**

Epithelial cells express various amino acid and oligopeptide transporter proteins that transport various amino acids and oligopeptide found in nutrients to facilitate their absorption. Therefore, designing a therapeutic drug with structural similarity with the natural substrate of the transporter proteins will help in transporting the molecule across the epithelium to the systemic circulation. This can also be achieved by attaching a natural substrate of the transporter proteins to the bioactive molecule [50]. This linkage will allow the recognition of the attached peptide by the transporter and its binding to the transporter. However, for this process to occur, the attached peptide should be enzymatically stable in the GIT. Otherwise, hydrolysis of the peptide before reaching the transporter will prevent the recognition of the molecule by the transporter, and thus, transportation will not happen. PepT1 is a transporter protein that plays a vital role in the oral delivery of biomolecules. PepT1 can transport dipeptides and tripeptides with varying degrees of substrate specificity. PepT1 is involved in the transport of peptidomimetic drugs such as acyclovir which resembles a dipeptide [51, 52].

Generally, only small molecules can be transported by membrane transport proteins. However, molecules with relatively larger sizes are usually transported by receptor-mediated endocytosis. Endocytosis involves the binding of the large molecule to a membrane receptor, and the resulting complex gets inside the cell. In some cases, the internalized molecule can be subjected to degradation by the lysosome. In other cases, the components of the complex are kept intact following internalization and exit the cell by exocytosis. Thus, these components are transported into the systemic circulation. This kind of receptor-mediated endocytosis is called transcytosis. Epidermal growth factor, vitamin B12, and immunoglobulins are some of the substances absorbed by the transcytosis [53]. It has been reported that by attaching a therapeutic protein or peptide (e.g., erythropoietin, α-interferon, etc.) to vitamin B12, the bioavailability of the protein or peptide can be enhanced [54].
