The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of peptides and peptide-related compounds, which are capable of crossing biological barriers with higher penetration efficiency comparing to their parent drugs. The HPPs are capable of being converted to parent drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs/HPCs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs/HPCs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.