Pharmacotherapeutics of SARS-CoV-2 Infections

Kevadiya, Bhavesh D.; Machhi, Jatin; Herskovitz, Jonathan; Oleynikov, Maxim D.; Blomberg, Wilson R.; Bajwa, Neha; Soni, Dhruvkumar; Das, Srijanee; Hasan, Mahmudul; Patel, Milankumar; Senan, Ahmed M.; Gorantla, Santhi; McMillan, Jo Ellyn; Edagwa, Benson; Eisenberg, Robert; Gurumurthy, Channabasavaiah B.; Reid, St Patrick; Punyadeera, Chamindie; Chang, Linda; Gendelman, Howard E.

doi:10.1007/s11481-020-09968-x

Cited by 12 publications

(10 citation statements)

References 201 publications

(205 reference statements)

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“…Currently used detection procedures are based on RT-PCR applied to viral RNA or on testing for the presence of antibodies in a serum sample. The former applies to current infections, the latter to prior infections [38]. Other approaches are based on biosensors using electrical or optical methods [39].…”

Section: Discussionmentioning

confidence: 99%

Using wide biological pores to cap and contain the COVID-19 spike protein

Sampath¹

2021

Preprint

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Geometric analysis shows that the spike (S) protein in the COVID-19 virus (SARS-Cov-2) can fully or partially enter into the channel of a wide biological pore like perforin (PFN) or streptolysin (SLO) when the latter is anchored in a bilayer lipid membrane. The PFN channel is a β barrel formed from multiple monomers, for example a ~14 nm diameter channel is formed from 22 monomers. Coincidentally the wide canopy of S (which has three identical chains) has an enclosing diameter of ~14 nm. While inside the channel peripheral residues in the canopy may bind with residues on the pore side of the barrel. If there are no adverse cross-reactions this would effectively prevent S from interacting with a target cell. Calculations with data obtained from PDB and other sources show that there are ~12 peripheral residue triples in S within a circle of diameter ~14 nm that can potentially bind with 22 exposed residues in each barrel monomer. The revised Miyazawa-Jernighan matrix is used to calculate the binding energy of canopy-PFN barrel residue pairs. The results show a large number of binding pairs over distances of up to 38 Å into the pore. This geometric view of capture and containment points to the possibility of using biological pores to neutralize SARS-Cov-2 in its many variant forms. Some necessary conditions that must be satisfied for such neutralization to occur are noted. A wide pore (such as PFN or SLO) can also be used in an electrolytic cell to detect the presence of SARS-Cov-2, which, by blocking the pore would cause a near total blockade of the base current (the ionic current in a fully open pore).

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Section: Discussionmentioning

confidence: 99%

Using wide biological pores to cap and contain the COVID-19 spike protein

Sampath¹

2021

Preprint

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“…In less than two years, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), has infected over 350 million people, killed over 5.5 million people, overwhelmed the global healthcare infrastructure, and unprecedentedly paused the world’s workforce and economies. Therefore, it is imperative to prepare downstream medical opportunities for therapeutic interventions [ 160 ]. While there are currently highly efficacious avenues for preventative care (upstream medicine), drugs that increase health outcomes in patients that are suffering from severe forms of COVID-19 (downstream medicine) remain undefined [ 161 ].…”

Section: The Use Of Prodrugs For Infectious Diseasesmentioning

confidence: 99%

Prodrug Therapies for Infectious and Neurodegenerative Diseases

et al. 2022

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Prodrugs are bioreversible drug derivatives which are metabolized into a pharmacologically active drug following chemical or enzymatic modification. This approach is designed to overcome several obstacles that are faced by the parent drug in physiological conditions that include rapid drug metabolism, poor solubility, permeability, and suboptimal pharmacokinetic and pharmacodynamic profiles. These suboptimal physicochemical features can lead to rapid drug elimination, systemic toxicities, and limited drug-targeting to disease-affected tissue. Improving upon these properties can be accomplished by a prodrug design that includes the careful choosing of the promoiety, the linker, the prodrug synthesis, and targeting decorations. We now provide an overview of recent developments and applications of prodrugs for treating neurodegenerative, inflammatory, and infectious diseases. Disease interplay reflects that microbial infections and consequent inflammation affects neurodegenerative diseases and vice versa, independent of aging. Given the high prevalence, personal, social, and economic burden of both infectious and neurodegenerative disorders, therapeutic improvements are immediately needed. Prodrugs are an important, and might be said a critical tool, in providing an avenue for effective drug therapy.

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“…Currently used detection procedures are based on RT-PCR applied to viral RNA or on testing for the presence of antibodies in a serum sample. The former applies to current infections, the latter to prior ones [35]. Other approaches are based on biosensors that use electrical or optical methods [36].…”

Section: Sars-cov-2 Virus Detection and Quantification With Wide Pores In An Electrolytic Cellmentioning

confidence: 99%

Using wide biological pores to cap and contain the COVID-19 spike protein

Sampath¹

2021

Preprint

View full text Add to dashboard Cite

Geometric analysis shows that the spike (S) protein in the COVID-19 virus (SARS-Cov-2) can fully or partially enter into the channel of a wide biological pore like perforin (PFN) or streptolysin (SLO) when the latter is anchored in a bilayer lipid membrane. The PFN channel is a β barrel formed from multiple monomers, for example a ~14 nm diameter channel is formed from 22 monomers. Coincidentally the wide canopy of S (which has three identical chains) has an enclosing diameter of ~14 nm. While inside the channel peripheral residues in the canopy may bind with residues on the pore side of the barrel. If there are no adverse cross-reactions this would effectively prevent S from interacting with a target cell. Calculations with data obtained from PDB and other sources show that there are ~12 peripheral residue triples in S within a circle of diameter ~14 nm that can potentially bind with 22 exposed residues in each barrel monomer. The revised Miyazawa-Jernighan matrix is used to calculate the binding energy of canopy-PFN barrel residue pairs. The results show a large number of binding pairs over distances of up to 38 Å into the pore. This geometric view of capture and containment points to the possibility of using biological pores to neutralize SARS-Cov-2 in its many variant forms. Some necessary conditions that must be satisfied for such neutralization to occur are noted. A wide pore (such as PFN or SLO) can also be used in an electrolytic cell to detect the presence of SARS-Cov-2, which would cause a large-sized blockade of the base current (the ionic current in a fully open pore). It can further be used to quantify the virus level in the sample. Solid-state pores, which have several advantages over biological ones, can be used instead; immune rejection is not an issue and there is no need for the spike or the virus to bind to the pore.

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Pharmacotherapeutics of SARS-CoV-2 Infections

Cited by 12 publications

References 201 publications

Using wide biological pores to cap and contain the COVID-19 spike protein

Using wide biological pores to cap and contain the COVID-19 spike protein

Prodrug Therapies for Infectious and Neurodegenerative Diseases

Using wide biological pores to cap and contain the COVID-19 spike protein

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