Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Independent trials indicate that either oral Zn²⁺ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn²⁺ deficit is a known risk factor for both COVID-19 and non-infectious inflammation. Most dietary Zn²⁺ is not absorbed. Metformin is a naked ligand that presumably increases intestinal Zn²⁺ bioavailability and active absorption by cation transporters known to transport metformin. Intracellular Zn²⁺ provides a natural buffer of many protease reactions; the variable “set point” is determined by Zn²⁺ regulation or availability. A Zn²⁺-interactive protease network is suggested here. The two viral cysteine proteases are therapeutic targets against COVID-19. Viral and many host proteases are submaximally inhibited by exchangeable cell Zn²⁺. Inhibition of cysteine proteases can improve COVID-19 outcomes and non-infectious inflammation. Metformin reportedly enhances the natural moderating effect of Zn²⁺ on bioassayed proteome degradation. Firstly, the dissociable metformin–Zn²⁺ complex could be actively transported by intestinal cation transporters; thereby creating artificial pathways of absorption and increased body Zn²⁺ content. Secondly, metformin Zn²⁺ coordination can create a non-natural protease inhibitor independent of cell Zn²⁺ content. Moderation of peptidolytic reactions by either or both mechanisms could slow (a) viral multiplication (b) viral invasion and (c) the pathogenic host inflammatory response. These combined actions could allow development of acquired immunity to clear the infection before life-threatening inflammation. Nirmatrelvir (Paxlovid®) opposes COVID-19 by selective inhibition the viral main protease by a Zn²⁺-independent mechanism. Pending safety evaluation, predictable synergistic benefits of metformin and Zn²⁺, and perhaps metformin/Zn²⁺/Paxlovid® co-administration should be investigated.