PMID- 34901357
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 2352-3530 (Electronic)
IS  - 2352-3522 (Print)
IS  - 2352-3522 (Linking)
VI  - 21
DP  - 2022 Aug
TI  - Using thermodynamic equilibrium models to predict the effect of antiviral agents 
      on infectivity: Theoretical application to SARS-CoV-2 and other viruses.
PG  - 100198
LID - 10.1016/j.mran.2021.100198 [doi]
AB  - Thermodynamic equilibrium models predict the infectivity of novel and emerging 
      viruses using molecular data including the binding affinity of the virus to the 
      host cell (as represented by the association constant K(a_virus_T)) and the 
      probability, p(virogenesis), of the virus replicating after entry to the cell. 
      Here those models are adapted based on the principles of ligand binding to 
      macromolecules to assess the effect on virus infectivity of inhibitor molecules 
      which target specific proteins of the virus. Three types of inhibitor are 
      considered using the thermodynamic equilibrium model for severe acute respiratory 
      syndrome coronavirus 2 (SARS-CoV-2) infection of the human lung with parameters 
      for the strength and nature of the interaction between the target virus protein 
      and the inhibitor molecule. The first is competitive inhibition of the SARS-CoV-2 
      spike glycoprotein (SGP) trimer binding to its human angiotensin converting 
      enzyme 2 (ACE2) receptor by unfractionated heparin (UFH). Using a novel approach 
      presented here, a value of K(a_virus_T) = 3.53 x 10(17) M(-1) is calculated for 
      SARS-CoV-2 from the IC(50) for inhibition by UFH of SARS-CoV-2 plaque formation 
      in cell culture together with the dissociation constant K(VI) of 0.73 x 10(-10) M 
      reported for heparin binding to SARS-CoV-2 SGP trimer. Such a high K(a_virus_T) 
      limits the effectiveness of competitive inhibitors such as UFH. The second is the 
      attachment of a nanoparticle such as a zinc oxide tetrapod (ZnOT) to the virus 
      shell as for herpes simplex virus (HSV). The increase in molecular weight through 
      ZnOT attachment is predicted to decrease K(a_virus_T) by orders of magnitude by 
      making the entropy change (DeltaS(a_immob)) on immobilisation of the ZnOT:virus 
      complex on cell binding more negative than for the virus alone. According to the 
      model, ZnOT acts synergistically with UFH at the IC(50) of 33 mug/cm(3) which 
      together decrease viral infectivity by 61,000-fold compared to the two-fold and 
      three-fold decreases predicted for UFH alone at the IC(50) and for ZnOT alone 
      respectively. According to the model here, UFH alone at its peak deliverable dose 
      to the lung of 1,000 mug/cm(3) only decreases infectivity by 31-fold. Practicable 
      approaches to target and decrease DeltaS(a_immob) for respiratory viruses should 
      therefore be considered. The combination of decreasing DeltaS(a_immob) together with 
      blocking the interaction of virus surface protein with its host cell receptor may 
      achieve synergistic effects for faecal-oral viruses and HSV. The third is 
      reversible noncompetitive inhibition of the viral main protease (M(pro)) for 
      which the decrease in p(virogenesis) is assumed to be proportional to the 
      decrease in enzyme activity as predicted by enzyme kinetic equations for a given 
      concentration of inhibitor which binds to M(pro) with dissociation constant K(i). 
      Virologists reporting viral inhibition studies are urged to report the 
      concentration of cells in the cell culture experiment as this is a key parameter 
      in estimating K(a_virus_T) here.
CI  - (c) 2021 Elsevier B.V. All rights reserved.
FAU - Gale, Paul
AU  - Gale P
AD  - Independent Scientist, 15 Weare Close, Portland, Dorset, DT5 1JP, UK.
LA  - eng
PT  - Journal Article
DEP - 20211204
PL  - Netherlands
TA  - Microb Risk Anal
JT  - Microbial risk analysis
JID - 101728821
PMC - PMC8642839
OTO - NOTNLM
OT  - SARS-CoV-2
OT  - drug
OT  - infection
OT  - inhibitor
OT  - risk
COIS- None declared.
EDAT- 2021/12/14 06:00
MHDA- 2021/12/14 06:01
PMCR- 2021/12/04
CRDT- 2021/12/13 18:11
PHST- 2021/10/07 00:00 [received]
PHST- 2021/11/16 00:00 [revised]
PHST- 2021/11/18 00:00 [accepted]
PHST- 2021/12/14 06:00 [pubmed]
PHST- 2021/12/14 06:01 [medline]
PHST- 2021/12/13 18:11 [entrez]
PHST- 2021/12/04 00:00 [pmc-release]
AID - S2352-3522(21)00040-2 [pii]
AID - 100198 [pii]
AID - 10.1016/j.mran.2021.100198 [doi]
PST - ppublish
SO  - Microb Risk Anal. 2022 Aug;21:100198. doi: 10.1016/j.mran.2021.100198. Epub 2021 
      Dec 4.