Dan Shu1, Fengmei Pi1, Chi Wang2, Peng Zhang3, Peixuan Guo1. 1. Department of Pharmaceutical Sciences, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. 2. Department of Biostatistics & Nanobiotechnology Center, University of Kentucky, Lexington, KY 40536, USA. 3. Department of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USA.
Abstract
AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number. METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui's Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population. RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with stoichiometry 1000 > 6 > 1. Complete inhibition of virus replication was found when Z = 6. CONCLUSION: Drug inhibition potency depends on the stoichiometry of the targeted components of the biocomplex or nanomachine. The inhibition effect follows a power function of the stoichiometry of the target biocomplex.
AIMS: To find methods for potent drug development by targeting to biocomplex with high copy number. METHODS: Phi29 DNA packaging motor components with different stoichiometries were used as model to assay virion assembly with Yang Hui's Triangle [Formula: see text], where Z = stoichiometry, M = drugged subunits per biocomplex, p and q are the fraction of drugged and undrugged subunits in the population. RESULTS: Inhibition efficiency follows a power function. When number of drugged subunits to block the function of the complex K = 1, the uninhibited biocomplex equals q(z), demonstrating the multiplicative effect of stoichiometry on inhibition with stoichiometry 1000 > 6 > 1. Complete inhibition of virus replication was found when Z = 6. CONCLUSION: Drug inhibition potency depends on the stoichiometry of the targeted components of the biocomplex or nanomachine. The inhibition effect follows a power function of the stoichiometry of the target biocomplex.
Authors: Lei Sun; Lindsey N Young; Xinzheng Zhang; Sergei P Boudko; Andrei Fokine; Erica Zbornik; Aaron P Roznowski; Ian J Molineux; Michael G Rossmann; Bentley A Fane Journal: Nature Date: 2013-12-15 Impact factor: 49.962