Discovery of a new method for potent drug development using power function of stoichiometry of homomeric biocomplexes or biological nanomotors

Abstract

Introduction: Multidrug resistance and the appearance of incurable diseases inspire the quest for potent therapeutics.

Areas covered: We review a new methodology in designing potent drugs by targeting multi-subunit homomeric biological motors, machines or complexes with Z > 1 and K = 1, where Z is the stoichiometry of the target, and K is the number of drugged subunits required to block the function of the complex. The condition is similar to a series electrical circuit of Christmas decorations: failure of one light bulb causes the entire lighting system to lose power. In most multi-subunit, homomeric biological systems, a sequential coordination or cooperative action mechanism is utilized, thus K equals 1. Drug inhibition depends on the ratio of drugged to non-drugged complexes. When K = 1, and Z > 1, the inhibition effect follows a power law with respect to Z, leading to enhanced drug potency. The hypothesis that the potency of drug inhibition depends on the stoichiometry of the targeted biological complexes was recently quantified by Yang-Hui’s Triangle (or binomial distribution), and proved using a highly sensitive in vitro phi29 viral DNA packaging system. Examples of targeting homomeric bio-complexes with high stoichiometry for potent drug discovery are discussed.

Expert opinion: Biomotors with multiple subunits are widespread in viruses, bacteria and cells, making this approach generally applicable in the development of inhibition drugs with high efficiency.

Keywords:

• antibacterial
• antivirus
• binomial distribution
• cancer drug development
• drug development
• drug target
• hexameric ATPase
• phi29 dsDNA packaging motor
• viral assembly

Declaration of interest

P Guo was supported by NIH grants NIH/R01 EB012135 and NIH/U01 CA151648. P Guo’s Endowed Chair in Nanobiotechnology position is funded by the William Fairish Endowment Fund. P Guo is a co-founder of Biomotor and RNA Nanotech Development Co. Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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