Why re-purposing HIV drugs Lopinavir/ritonavir to inhibit the SARS-Cov2 protease probably wont work - but re-purposing Ribavirin might since it has a very similar binding site within the RNA-polymerase

Mapping Intimacies ◽

10.31219/osf.io/ax98f ◽

2020 ◽

Cited By ~ 1

Author(s):

Sandeep Chakraborty

Keyword(s):

Rna Polymerase ◽

Binding Site ◽

Protease Inhibitors ◽

Cysteine Protease ◽

Cysteine Proteases ◽

Aspartic Protease ◽

Catalytic Site ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Hiv Drugs

A trial of Lopinavir/Ritonavir in adults hospitalized with severe Covid-19 has not shown significant dif- ference [1]. This is not surprising considering that the HIV aspartic protease - which Lopinavir/Ritonavir inhibit (Table 1) - is quite different from the cysteine proteases in SARS-Cov2.A review explains this well - ‘it is debatable whether HIV protease inhibitors could effectively inhibit the 3-chymotrypsin-like and papain-like proteases of 2019-nCoV. HIV protease belongs to the aspartic protease family, whereas the two coronavirus proteases are from the cysteine protease family. Furthermore, HIV protease inhibitors were specifically optimized to fit the C2 symmetry in the catalytic site of the HIV protease dimer, but this C2-symmetric pocket is absent in coronavirus proteases. If HIV protease inhibitors alter host pathways to indirectly interfere with coronavirus infections, their potency remains a concern.’ [2].However, using known structures of the SARS-Cov2, one can dock molecules, and thus re-purpose existing drugs.

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HIV Protease Inhibitors Act as Competitive Inhibitors of the Cytoplasmic Glucose Binding Site of GLUTs with Differing Affinities for GLUT1 and GLUT4

PLoS ONE ◽

10.1371/journal.pone.0025237 ◽

2011 ◽

Vol 6 (9) ◽

pp. e25237 ◽

Cited By ~ 47

Author(s):

Richard C. Hresko ◽

Paul W. Hruz

Keyword(s):

Binding Site ◽

Protease Inhibitors ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Glucose Binding ◽

Competitive Inhibitors

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Antiapoptotic mechanism of HIV protease inhibitors: preventing mitochondrial transmembrane potential loss

Blood ◽

10.1182/blood.v98.4.1078 ◽

2001 ◽

Vol 98 (4) ◽

pp. 1078-1085 ◽

Cited By ~ 74

Author(s):

Barbara N. Phenix ◽

Julian J. Lum ◽

Zelin Nie ◽

Jaime Sanchez-Dardon ◽

Andrew D. Badley

Keyword(s):

Protease Inhibitors ◽

Transmembrane Potential ◽

Mitochondrial Transmembrane Potential ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Caspase Activity ◽

Potential Loss ◽

Apoptotic Pathways ◽

Hiv Drugs

Treatment of cells with the HIV drugs ritonavir, saquinavir, or nelfinavir (Nfv) inhibits apoptosis induced by a variety of stimuli. Because these drugs are protease inhibitors, they have been postulated to inhibit apoptosis by blocking caspase activity. This study shows that Nfv has no effect on caspase activity or on the transcription or synthesis of a variety of apoptosis regulatory molecules. Instead, Nfv inhibits mitochondrial transmembrane potential loss (Δψm) and the subsequent release of apoptotic mediators. Consequently, the antiapoptotic effects of Nfv are restricted to apoptotic pathways that involve Δψm.

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Repositioning HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors for the treatment of SARS-CoV-2 infection and COVID-19

European Journal of Clinical Pharmacology ◽

10.1007/s00228-021-03108-x ◽

2021 ◽

Author(s):

Nils von Hentig

Keyword(s):

Clinical Trials ◽

Rna Polymerase ◽

Protease Inhibitors ◽

Study Design ◽

Drug Repositioning ◽

Rna Virus ◽

Antiviral Treatment ◽

Hiv Protease ◽

Hiv Protease Inhibitors ◽

Polymerase Inhibitors

Abstract Aims SARS-CoV-2 is a single-stranded RNA virus which is part of the ß-coronavirus family (like SARS 2002 and MERS 2012). The high prevalence of hospitalization and mortality, in addition to the lack of vaccines and therapeutics, forces scientists and clinicians around the world to evaluate new therapeutic options. One strategy is the repositioning of already known drugs, which were approved drugs for other indications. Subject and method SARS-CoV-2 entry inhibitors, RNA polymerase inhibitors, and protease inhibitors seem to be valuable targets of research. At the beginning of the pandemic, the ClinicalTrials.gov webpage listed n=479 clinical trials related to the antiviral treatment of SARS-CoV-2 (01.04.2020, “SARS-CoV-2,” “COVID-19,” “antivirals,” “therapy”), of which n=376 are still accessible online in January 2021 (10.01.2021). Taking into account further studies not listed in the CTG webpage, this narrative review appraises HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors as promising candidates for the treatment of COVID-19. Results Lopinavir/ritonavir, darunavir/cobicistat, remdesivir, tenofovir-disoproxilfumarate, favipriravir, and sofosbuvir are evaluated in clinical studies worldwide. Study designs show a high variability and results often are contradictory. Remdesivir is the drug, which is deployed in nearly 70% of the reviewed clinical trials, followed by lopinavir/ritonavir, favipiravir, ribavirine, and sofosbuvir. Discussion This review discusses the pharmacological/clinical background and questions the rationale and study design of clinical trials with already approved HIV protease inhibitors and nucleos(t)ide RNA polymerase inhibitors which are repositioned during the SARS-CoV-2 pandemic worldwide. Proposals are made for future study design and drug repositioning of approved antiretroviral compounds.

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