Technology
Chimerix’s proprietary lipid technology ProLipTagTM is used to covalently modify a drug molecule so that it mimics a naturally occurring phospholipid metabolite. The lipid mimic can then utilize the natural uptake pathways in the gut to achieve a high oral availability. The design paradigm used to generate the mimic is shown in Figure 1.
Lysophosphatidylcholine (LPC, shown on the left in Figure 1) is a natural lipid metabolite that is readily absorbed intact from the small intestine and distributed in the blood and lymph throughout the body. The mimic (shown on the right in Figure 1) is formed by modifying the X and R groups on the lipid moiety and replacing the choline head group of LPC with a drug. The drug is connected to the modified lipid molecule with a linker, L. By chemically modifying the R and X groups, the distribution of the mimic to various organ systems can be controlled. The linker can be chosen to influence the rate of release of the drug in the targeted organ system. Although a linker can be chosen to facilitate quick release into the blood following uptake from the gut, one can be chosen that is cleaved by intracellular enzymes. In this case the lipid can also facilitate uptake into the target cell, as is illustrated for the case of cidofovir (CDV) below.
CMX001 is a lipid mimic of cidofovir formed by linking a lipid 3-hexadecyloxy-1-propanol, to the phosphonate group of cidofovir (depicted as HDP-CDV in Figure 2)
Efficient Cellular Uptake leads to better Efficacy in Vitro
The cellular uptake of CDV has been shown to occur by fluid phase endocytosis. The rate of in vitro drug uptake facilitated by this process is relatively slow, approximately 1.8% of the extracellular concentration per hour. Additionally, it has been suggested that the effectiveness of cidofovir may be variable among different cell types owing to the fact that fluid-phase endocytosis is cell cycle dependent and greatest during the G1 phase. CMX001 is designed to cross cellular membranes by passive diffusion (vida supra, Phospholipid Mimics Designed to Facilitate Uptake in the Small Intestine). Uptake by this mechanism should be more efficient and lead to a more rapid accumulation of cidofovir in the cytoplasm of the target cell. Once it has reached the cytoplasm, CDV is phosphorylated by host cell nucleoside kinases to form the active antiviral agent cidofovir diphosphate (CDV-PP), this information is depicted in Figure 2.
Figure 2
Our proprietary lipid prodrug technology was originally developed at the University of California at San Diego and the Veterans Administration Hospital in San Diego, CA and further developed into ProLipTagTM through Chimerix application and improvements of the technology, based on preclinical and clinical data.