Cathepsin L-selective inhibitors: A potentially promising treatment for COVID-19 patients.

Abstract:

:The widespread coronavirus SARS-CoV-2 has already infected over 4 million people worldwide, with a death toll over 280,000. Current treatment of COVID-19 patients relies mainly on antiviral drugs lopinavir/ritonavir, arbidol, and remdesivir, the anti-malarial drugs hydroxychloroquine and chloroquine, and traditional Chinese medicine. There are over 2,118 on-going clinical trials underway, but to date none of these drugs have consistently proven effective. Cathepsin L (CatL) is an endosomal cysteine protease. It mediates the cleavage of the S1 subunit of the coronavirus surface spike glycoprotein. This cleavage is necessary for coronavirus entry into human host cells, virus and host cell endosome membrane fusion, and viral RNA release for next round of replication. Here we summarize data regarding seven CatL-selective inhibitors that block coronavirus entry into cultured host cells and provide a mechanism to block SARS-CoV-2 infection in humans. Given the rapid growth of the SARS-CoV-2-positive population worldwide, ready-to-use CatL inhibitors should be explored as a treatment option. We identify ten US FDA-approved drugs that have CatL inhibitory activity. We provide evidence that supports the combined use of serine protease and CatL inhibitors as a possibly safer and more effective therapy than other available therapeutics to block coronavirus host cell entry and intracellular replication, without compromising the immune system.

journal_name

Pharmacol Ther

authors

Liu T,Luo S,Libby P,Shi GP

doi

10.1016/j.pharmthera.2020.107587

subject

Has Abstract

pub_date

2020-09-01 00:00:00

pages

107587

eissn

0163-7258

issn

1879-016X

pii

S0163-7258(20)30115-7

journal_volume

213

pub_type

杂志文章,评审
  • Complex regulation of thyroid hormone action: multiple opportunities for pharmacological intervention.

    abstract::The thyroid hormone (TH; 3,3',5,5'-tetra-iodothyronine and 3,3',5'-triiodothyronine) regulates growth, development, and critical metabolic functions. Thyroid diseases are among the most prevalent group of metabolic disorders in the Western world. TH exerts effects through complex biological pathways, which offer a wea...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/s0163-7258(02)00219-x

    authors: Shi YB,Ritchie JW,Taylor PM

    更新日期:2002-06-01 00:00:00

  • KRAS-related proteins in pancreatic cancer.

    abstract::Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, includ...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2016.09.003

    authors: Mann KM,Ying H,Juan J,Jenkins NA,Copeland NG

    更新日期:2016-12-01 00:00:00

  • Challenges and achievements in the therapeutic modulation of aquaporin functionality.

    abstract::Aquaporin (AQP) water and solute channels have basic physiological functions throughout the human body. AQP-facilitated water permeability across cell membranes is required for rapid reabsorption of water from pre-urine in the kidneys and for sustained near isosmolar water fluxes e.g. in the brain, eyes, inner ear, an...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2015.08.002

    authors: Beitz E,Golldack A,Rothert M,von Bülow J

    更新日期:2015-11-01 00:00:00

  • Astroglial neurotrophic and neurite-promoting factors.

    abstract::Astroglial cells express neurotrophic and/or neurite growth-promoting factors, including (a) peptide growth factors (e.g. nerve growth factors, ciliary neuronotrophic factor, fibroblast growth factor), (b) neurotransmitters (such as glutamate, neuropeptide Y), (c) cell adhesion molecules (e.g. N-CAM) and (d) extracell...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/0163-7258(94)00047-7

    authors: Müller HW,Junghans U,Kappler J

    更新日期:1995-01-01 00:00:00

  • Intestinal toxicity of non-steroidal anti-inflammatory drugs.

    abstract::We review the adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) on the small and large intestine. NSAIDs cause small intestinal inflammation in 65% of patients receiving the drugs long-term. The clinical implications of NSAID-induced enteropathy are that patients bleed and lose protein from the inflamma...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/0163-7258(94)90008-6

    authors: Bjarnason I,Macpherson AJ

    更新日期:1994-04-01 00:00:00

  • Cancer stem cells and chemoresistance: The smartest survives the raid.

    abstract::Chemoresistant metastatic relapse of minimal residual disease plays a significant role for poor prognosis of cancer. Growing evidence supports a critical role of cancer stem cell (CSC) behind the mechanisms for this deadly disease. This review briefly introduces the basics of the conventional chemotherapies, updates t...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2016.02.008

    authors: Zhao J

    更新日期:2016-04-01 00:00:00

  • The sphingosine kinase-1/sphingosine-1-phosphate axis in cancer: Potential target for anticancer therapy.

    abstract::Sphingolipid metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate (S1P), play many important roles in cellular activities. Ceramide and sphingosine inhibit cell proliferation and induce cell apoptosis while S1P has the opposite effect. Maintaining a metabolic balance of sphingolipids is essential for...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2018.10.011

    authors: Zheng X,Li W,Ren L,Liu J,Pang X,Chen X,Kang,Wang J,Du G

    更新日期:2019-03-01 00:00:00

  • Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy.

    abstract::Chemoresistance, radioresistance, and the challenge of achieving complete resection are major driving forces in the search for more robust and targeted anticancer therapies. Targeting the DNA damage response has recently attracted research interest, as these processes are enhanced in tumour cells. The major replicatio...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2020.107518

    authors: Gorecki L,Andrs M,Rezacova M,Korabecny J

    更新日期:2020-06-01 00:00:00

  • The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review.

    abstract::The 90-kDa molecular chaperone family (which comprises, among other proteins, the 90-kDa heat-shock protein, hsp90 and the 94-kDa glucose-regulated protein, grp94, major molecular chaperones of the cytosol and of the endoplasmic reticulum, respectively) has become an increasingly active subject of research in the past...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/s0163-7258(98)00013-8

    authors: Csermely P,Schnaider T,Soti C,Prohászka Z,Nardai G

    更新日期:1998-08-01 00:00:00

  • Drug uptake transporters in antiretroviral therapy.

    abstract::Current treatment of human immunodeficiency virus-1 (HIV-1) infection is effective, although it does not permanently suppress viral replication in all patients. Viral persistence, drug toxicity, and antiretroviral resistance are challenging barriers to successful treatment of HIV-1 infection. It has become increasingl...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2011.06.007

    authors: Minuesa G,Huber-Ruano I,Pastor-Anglada M,Koepsell H,Clotet B,Martinez-Picado J

    更新日期:2011-12-01 00:00:00

  • Novel pharmacological targets for the rhythm control management of atrial fibrillation.

    abstract::Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2011.08.002

    authors: Burashnikov A,Antzelevitch C

    更新日期:2011-12-01 00:00:00

  • Extracellular vesicles in cancer diagnostics and therapeutics.

    abstract::Cancer promotion, development, and malignant transformation is greatly influenced by cell-to-cell interactions in a complex tissue microenvironment. Cancer and stromal cells secrete soluble factors, as well as deport membrane-encapsulated structures, which actively contribute and mediate cell-to-cell interaction withi...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2021.107806

    authors: Shehzad A,Islam SU,Shahzad R,Khan S,Lee YS

    更新日期:2021-01-16 00:00:00

  • Dopamine D2 autoreceptor interactome: Targeting the receptor complex as a strategy for treatment of substance use disorder.

    abstract::Dopamine D2 autoreceptors (D2ARs), located in somatodendritic and axon terminal compartments of dopamine (DA) neurons, function to provide a negative feedback regulatory control on DA neuron firing, DA synthesis, reuptake and release. Dysregulation of D2AR-mediated DA signaling is implicated in vulnerability to substa...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2020.107583

    authors: Chen R,Ferris MJ,Wang S

    更新日期:2020-09-01 00:00:00

  • Molecular genetics of the renin-angiotensin system: implications for angiotensin II receptor blockade.

    abstract::Angiotensin II (Ang II) is the main effector hormone of the renin-angiotensin system (RAS). The pathogenesis of many cardiovascular diseases, including heart failure and hypertension, appear to be related to Ang II production. The generation of Ang II involves angiotensin-converting enzyme (ACE) in circulating and tis...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/s0163-7258(97)00021-1

    authors: Davis GK,Roberts DH

    更新日期:1997-01-01 00:00:00

  • Benzodiazepines, anxiety and immunity.

    abstract::Experimental and clinical studies suggest that the central and peripheral benzodiazepine (BDZ) receptors together with their ligands form the molecular basis of a novel regulatory network that contributes to the effects of anxiety on immune status. The peripheral-type receptors located on phagocytes and glial cells ap...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/s0163-7258(97)00055-7

    authors: Zavala F

    更新日期:1997-09-01 00:00:00

  • PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders.

    abstract::Neurodegenerative diseases represent some of the most devastating neurological disorders, characterized by progressive loss of the structure and function of neurons. Current therapy for neurodegenerative disorders is limited to symptomatic treatment rather than disease modifying interventions, emphasizing the desperat...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2020.107705

    authors: Jamwal S,Blackburn JK,Elsworth JD

    更新日期:2020-10-09 00:00:00

  • Use of biologics to treat acute exacerbations and manage disease in asthma, COPD and IPF.

    abstract::A common feature of chronic respiratory disease is the progressive decline in lung function. The decline can be indolent, or it can be accelerated by acute exacerbations, whereby the patient experiences a pronounced worsening of disease symptoms. Moreover, acute exacerbations may also be a marker of insufficient disea...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2016.11.003

    authors: Murray LA,Grainge C,Wark PA,Knight DA

    更新日期:2017-01-01 00:00:00

  • A novel paradigm for therapeutic basis of advanced heart failure--assessment by gene therapy.

    abstract::The precise mechanism(s) of the progression of advanced heart failure (HF) should be determined to establish strategies for its treatment or prevention. Based on pathological, molecular, and physiological findings in 3 animal models and human cases, we propose a novel scheme that a vicious cycle formed by increased sa...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2004.12.006

    authors: Kawada T,Masui F,Kumagai H,Koshimizu M,Nakazawa M,Toyo-Oka T

    更新日期:2005-07-01 00:00:00

  • The importance of circadian rhythms on drug response in hypertension and coronary heart disease--from mice and man.

    abstract::The cardiovascular system is highly organised in time; blood pressure (BP), heart rate (HR), peripheral resistance, pressure and the release/activity of vasodilating hormones all display pronounced circadian variations. Pathophysiological events within the cardiovascular system are also not random, as shown for instan...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2005.11.008

    authors: Lemmer B

    更新日期:2006-09-01 00:00:00

  • A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity.

    abstract::Drug candidate and toxicity screening processes currently rely on results from early-stage in vitro cell-based assays expected to faithfully represent essential aspects of in vivo pharmacology and toxicology. Several in vitro designs are optimized for high throughput to benefit screening efficiencies, allowing the ent...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2012.01.001

    authors: Astashkina A,Mann B,Grainger DW

    更新日期:2012-04-01 00:00:00

  • C-type natriuretic peptide in vascular physiology and disease.

    abstract::Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed t...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2004.08.011

    authors: Scotland RS,Ahluwalia A,Hobbs AJ

    更新日期:2005-02-01 00:00:00

  • Does Thiazolidinedione therapy exacerbate fluid retention in congestive heart failure?

    abstract::The ever-growing global burden of congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM) as well as their co-existence necessitate that anti-diabetic pharmacotherapy will modulate the cardiovascular risk inherent to T2DM while complying with the accompanying restrictions imposed by CHF. The thiazolidinedio...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2016.09.007

    authors: Goltsman I,Khoury EE,Winaver J,Abassi Z

    更新日期:2016-12-01 00:00:00

  • Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.

    abstract::Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of ...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2014.04.004

    authors: Bose P,Dai Y,Grant S

    更新日期:2014-09-01 00:00:00

  • The birth of artemisinin.

    abstract::As the first-line antimalarial drugs, artemisinins gained wide acceptance after the emergence of resistance to chloroquine in the 1950s. Artemisinin-based drugs have saved lives, especially in developing countries. The discovery of artemisinin was unique, timely, and fascinating, and the benefits of artemisinin were w...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2020.107658

    authors: Ma N,Zhang Z,Liao F,Jiang T,Tu Y

    更新日期:2020-12-01 00:00:00

  • Short-term regulation of organic anion transporters.

    abstract::Organic anion transporters (OATs), which belong to the superfamily SLC22A, are key determinants in the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, and, therefore, are critical for the survival of mammalian species. Alteration in the function of th...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2009.08.002

    authors: Duan P,You G

    更新日期:2010-01-01 00:00:00

  • Metabolic syndrome and associated cardiovascular risk factors in the treatment of persons with human immunodeficiency virus and severe mental illness.

    abstract::Over the past 15 years, novel pharmacologic treatments for the management of HIV/AIDS and severe mental illness have changed the prognosis and quality of life for millions of patients throughout the world. In HIV-infected patients, highly active antiretroviral therapy (HAART) has altered this epidemic in many countrie...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2009.07.004

    authors: Vergara-Rodriguez P,Vibhakar S,Watts J

    更新日期:2009-12-01 00:00:00

  • Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury.

    abstract::Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation ...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2018.01.007

    authors: Liu YY,Brent GA

    更新日期:2018-06-01 00:00:00

  • Endothelial dysfunction in cirrhosis and portal hypertension.

    abstract::Portal hypertension (PHT) is a common clinical syndrome associated with chronic liver diseases; it is characterized by a pathological increase in portal pressure. Pharmacotherapy for PHT is aimed at reducing both intrahepatic vascular tone and elevated splanchnic blood flow. Due to the altered hemodynamic profile in P...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/s0163-7258(01)00128-0

    authors: Cahill PA,Redmond EM,Sitzmann JV

    更新日期:2001-03-01 00:00:00

  • Interaction between nitric oxide and the cholinergic and sympathetic nervous system in cardiovascular control in humans.

    abstract::Evidence has accumulated indicating that the interaction between NO and the autonomic nervous system plays an important role in cardiovascular regulation, not only in experimental animals, but also in humans. NO interacts with the autonomic nervous system both at the central level and peripherally. In this review, we ...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2004.11.009

    authors: Sartori C,Lepori M,Scherrer U

    更新日期:2005-05-01 00:00:00

  • Immunotherapy in sepsis - brake or accelerate?

    abstract::Sepsis, a life threating syndrome characterized by organ failure after infection, is the most common cause of death in hospitalized patients. The treatment of sepsis is generally supportive in nature, involving the administration of intravenous fluids, vasoactive substances and oxygen plus antibiotics to eliminate the...

    journal_title:Pharmacology & therapeutics

    pub_type: 杂志文章,评审

    doi:10.1016/j.pharmthera.2020.107476

    authors: Steinhagen F,Schmidt SV,Schewe JC,Peukert K,Klinman DM,Bode C

    更新日期:2020-04-01 00:00:00