Multi-homosubunit dsRNA/dsDNA virus genome packaging nanomotors with sequential revolving mechanisms for potent drug development

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Abstract
The emergence of new viral diseases and viral drug resistance presents a critical challenge in human health. Recent structural and mechanistic studies have revealed remarkable parallels and structural similarities among viral dsDNA- and dsRNA-packaging motors, ATPases, ATP-binding cassette drug transporters (ABCs), and ATP-generating machines, particularly in their asymmetrical, multi-homosubunit hexameric arrangement and sequential revolving mechanisms. Both dsDNA and dsRNA viruses package their genomes into preformed hexameric ATPase motors. This review examines how understanding these evolutionarily convergent nanomotors can inform novel therapeutic strategies. We first review the structures and mechanisms of representative ds-genome packaging motors from bacteriophage phi29, human herpesvirus, dsRNA viruses, cystoviruses, and other systems. We systematically compare viral DNA packaging motors with ABC transporters, cataloguing over 30 major ATPase systems across eight functional categories. Their commonalities—multi-homosubunit architecture with sequential revolving mechanisms regulated by ATP—are summarized and classified by therapeutic potential. We then describe a novel drug development method targeting multi-homosubunit biomachines through the “Series-Circuit-Christmas-Bulb” mechanism, where Z > 1 (subunit stoichiometry) and K = 1 (drugged subunits needed for inhibition). Blocking one subunit disrupts the entire sequential chain, analogous to one single series-circuit Christmas lightbulb failure, disabling the entire strand. Mathematical validation using phi29 systems demonstrates 10 7 -10 8 fold inhibition efficiency. Practical examples include FDA-approved bedaquiline targeting bacterial F 1 F 0 ATPase for tuberculosis treatment and RNA nanoparticle-based delivery systems targeting P-glycoprotein for cancer drug resistance. The convergence of nano-structural insights, computational methods, and advanced delivery systems presents a unique framework for developing potent therapies against viral infections and drug resistance mechanisms.

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