Construction of a physical model of a farnesyltransferase-inhibitor complex: Insight into a novel therapy for Hutchinson-Guilford Progeria

Future Research Farnesyltransferase Inhibitors (FTIs) may be an effective treatment for progeria. However, this wouldn’t be considered a cure because it would interfere with other reactions that require farnesylation within the cell. Farnesylation functions in normal phenotypes to establish a functioning nuclear lamina. If farnesylation is interfered with, then necessary proteins will not be made available. Abstract: The Riverside High School SMART Team (Students Modeling A Research Topic) created a 3D physical model of a farnesyltransferase (FTase)-inhibitor complex and discussed its significance in the development of a novel therapy for Hutchinson-Guilford Progeria. Farnesyltransferase inhibitors (FTIs) were originally designed as anti-cancer drugs, but recently have been shown to slow premature aging resulting from Progeria . This premature aging syndrome is caused by a mutation that affects processing of the Lamin A protein, a component of the nuclear lamina. A farnesylated prelamin intermediate accumulates, which in turn interferes with the assembly of a functional nuclear lamina. Farnesylation of prelamin A occurs on a CaaX box motif by the FTase. One class of FTIs structurally mimics the CaaX motif thereby inhibiting the enzyme. Inhibition of Lamin A farnesylation prevents the accumulation of farnesyl-prelamin A and inhibition of lamina assembly. This surprising discover has given clinicians the first drug to treat this rare, but deadly premature aging syndrome. By studying the structure of FTIs bound to FTase, more new specific drugs might be found.