From quantum‐derived principles underlying cysteine reactivity to combating the COVID‐19 pandemic. (5th March 2022)

• Record Type: Journal Article
• Authors: Mazmanian, Karine; Chen, Ting; Sargsyan, Karen; Lim, Carmay
• Is Part Of: Wiley interdisciplinary reviews. Volume 12:Number 5(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-03-05
• Subjects: COVID‐19 -- cysteine reactivity -- labile Zn‐sites -- SARS‐CoV‐2 -- structural Zn; Chemistry, Physical and theoretical -- Periodicals; Cheminformatics -- Periodicals; Biochemistry -- Periodicals; 541.220285
• DOI: 10.1002/wcms.1607
• Languages: English
• ISSNs: 1759-0876

Abstract

Abstract: The COVID‐19 pandemic poses a challenge in coming up with quick and effective means to counter its cause, the SARS‐CoV‐2. Here, we show how the key factors governing cysteine reactivity in proteins derived from combined quantum mechanical/continuum calculations led to a novel multi‐targeting strategy against SARS‐CoV‐2, in contrast to developing potent drugs/vaccines against a single viral target such as the spike protein. Specifically, they led to the discovery of reactive cysteines in evolutionary conserved Zn 2+ ‐sites in several SARS‐CoV‐2 proteins that are crucial for viral polypeptide proteolysis as well as viral RNA synthesis, proofreading, and modification. These conserved, reactive cysteines, both free and Zn 2+ ‐bound, can be targeted using the same Zn‐ejector drug (disulfiram/ebselen), which enables the use of broad‐spectrum anti‐virals that would otherwise be removed by the virus's proofreading mechanism. Our strategy of targeting multiple, conserved viral proteins that operate at different stages of the virus life cycle using a Zn‐ejector drug combined with other broad‐spectrum anti‐viral drug(s) could enhance the barrier to drug resistance and antiviral effects, as compared to each drug alone. Since these functionally important nonstructural proteins containing reactive cysteines are highly conserved among coronaviruses, our proposed strategy has the potential to tackle future coronaviruses. This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis Structure and Mechanism > Computational Biochemistry and Biophysics Electronic Structure Theory > Density Functional Theory Abstract : We reveal the key factors controlling the reactivity of free and Zn‐bound Cys in proteins and apply them to identify reactive Cys in multiple, conserved SARS‐CoV‐2 domains that can be targeted by clinically safe drugs, disulfiram or ebselen, to inhibit viral polyprotein cleavage, and viral RNA replication/transcription.