![]() It is a membrane dipeptidase involved in the metabolism of glutathione, leukotriene D 4, and certain lactam antibiotics ( 25). So far, one vascular receptor for such organ-specific peptides has been identified molecularly. ![]() 1), suggesting that many, if not all, tissues put a signature on their vasculature that make that vascular bed unique in the body ( 24). ![]() Moreover, the new US government funding agency, Advanced Research Projects Agency for Health, recently named ZC-based drug targeting as an emerging focus area in medicine ( 17).Īnalyses of vascular heterogeneity in situ by in vivo screening of phage libraries has yielded peptides that selectively recognize the blood vessels of a single organ ( Fig. There are already several approved ligand-directed ZC drugs in the clinic and in clinical trials for the treatment of solid tumors ( 16), and drugs targeted to the liver for the treatment of various genetic and metabolic diseases are also on the market. The approach is commonly referred to a ligand-directed drug targeting and is gaining momentum. Drug delivery can be enhanced by linking a drug to a ZC ligand to specifically direct it to a ZC address related to the disease that the drug is treating. Thus, severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has recently been shown to use an RXXR motif (C-end Rule motif 10) to effect internalization into cells through neuropilin-1 (NRP-1) binding and the RGD cell attachment sequence ( 11) to bind to integrins ( 12– 15). The role of molecular ZCs in the entry of the SARS-CoV-2 and other viruses into cells ( 7) and targeted drug delivery ( 8, 9) have made ZCs topical in recent years. As the molecule is supposed to be able to serve as a recognition molecule for cells or molecules, it also must be expressed bound to the surface of the cells or their matrix. Also, the original metaphor of area codes in the telephone system has become ZCs of the postal system. The definition of molecular ZIP codes (ZCs) has since expanded beyond developmental biology and currently encompasses any molecule that the expression of which in the adult body is restricted to a certain cell type, tissue, organ, or pathological condition. Subsequent discovery of molecules that mediated cell–extracellular matrix and cell–cell recognition, provided a molecular basis for the hypothesis ( 4– 6). Observations such as spontaneous sorting of like from unlike sponge cells ( 1) and the navigation by growing retinal axons to their predetermined connections in the brain tectum ( 2) led to a hypothesis that “area code” molecules at cell surfaces guided the cells of the embryo to the appropriate place in the developing organism ( 3). What are “molecular ZIP codes”? The origins of this concept go back to the search for molecular explanation for precision and complexity of the formation of body structure during embryonal development.
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