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 multisubunit, 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 nondrugged 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.

Construction of Asymmetrical Hexameric Biomimetic Motors with Continuous Single-Directional Motion by Sequential Coordination

“…However, incorporation of only one mutant, either pRNAdCCA (with CCA bulge deletion, Figure , red box) or pRNAtrun (truncated at the 5′‐ and 3′‐ends, Figure , blue box), into the hexameric loop completely obliterated the motor function in DNA packaging activity. The fact that one inactive pRNA is sufficient to block the function of the entire motor has been defined as K = 1 . In binomial distribution, K = 1 for the hexametric RNA ring implies that six RNA molecules worked sequentially …”

“…The fact that one inactive pRNA is sufficient to block the function of the entire motor has been defined as K = 1 . In binomial distribution, K = 1 for the hexametric RNA ring implies that six RNA molecules worked sequentially …”

High resolution structure of hexameric herpesvirus DNA-packaging motor elucidates revolving mechanism and ends 20-year fervent debate

“…The mechanism of dsDNA processing can be extended to ATPase motors in protein processing, peptide transportation, and trafficking of other macromolecules. The elucidation of structure and mechanism of the asymmetrical hexameric dsDNA transportation motor with a revolving mechanism will provide a prototype for the construction of a revolving motor or nanomotor with high efficiency in energy conversion and provide an excellent substrate for the design of potent inhibitory drugs to treat cancer and other diseases (Goldner et al, 2011;Shu et al, 2015;Pi et al, 2016a;Pi et al, 2016b;Acosta et al, 2020). The revolving mechanism for the motion of objects along a helical chain provides a hint at the design of new moving machines along a track, such as that used by roller coasters, trolley cars or rocket launchers to depart from a helical track without the need for the object to rotate.…”

Channel of viral DNA packaging motor for real time kinetic analysis of peptide oxidation states

“…The ingenious design of viral DNA packaging motors and their intriguing mechanism of action has triggered a wide range of interests among scientists in many different areas[1–3]. The portal protein is one of the essential components of the viral packaging motors with a turbine-like shape[4,5].…”