Rega Institute for Medical Research

Leuven, Belgium

Rega Institute for Medical Research

Leuven, Belgium

The Rega Institute for Medical Research is a Belgian scientific establishment that is part of the Catholic University of Leuven in central Belgium. The Rega Institute is an interfacultary biomedical research institute of the Catholic University of Leuven and consists of departments of medicine and pharmacology. Wikipedia.


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De Clercq E.,Rega Institute for Medical Research
Biochemical Pharmacology | Year: 2015

Within less than a year after its epidemic started (in December 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a number of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chemical substances, i.e. neplanocin A derivatives (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compounds that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compounds active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae. © 2014 Elsevier Inc. All rights reserved.


De Clercq E.,Rega Institute for Medical Research
Medicinal Research Reviews | Year: 2015

Antiviral drug development has often followed a curious meandrous route, guided by serendipity rather than rationality. This will be illustrated by ten examples. The polyanionic compounds (i) polyethylene alanine (PEA) and (ii) suramin were designed as an antiviral agent (PEA) or known as an antitrypanosomal agent (suramin), before they emerged as, respectively, a depilatory agent, or reverse transcriptase inhibitor. The 2′,3′-dideoxynucleosides (ddNs analogues) (iii) have been (and are still) used in the "Sanger" DNA sequencing technique, although they are now commercialized as nucleoside reverse transcriptase inhibitors (NRTIs) in the treatment of HIV infections. (E)-5-(2-Bromovinyl)-2′-deoxyuridine (iv) was discovered as a selective anti-herpes simplex virus compound and is now primarily used for the treatment of varicella-zoster virus infections. The prototype of the acyclic nucleoside phosphonates (ANPs), (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], (v) was never commercialized, although it gave rise to several marketed products (cidofovir, adefovir, and tenofovir). 1-[2-(Hydroxyethoxy)methyl]-6-(phenylthio)thymine (vi) and TIBO (tetrahydroimidazo[4,5,1-jk][1,4-benzodiazepin-2(1H)]-one and -thione) (vii) paved the way to a number of compounds (i.e., nevirapine, delavirdine, etravirine, and rilpivirine), which are now collectively called non-NRTIs. The bicyclam AMD3100 (viii) was originally described as an anti-HIV agent before it became later marketed as a stem cell mobilizer. The S-adenosylhomocysteine hydrolase inhibitors (ix), while active against a broad range of (-)RNA viruses and poxviruses may be particularly effective against Ebola virus, and for (x) the O-ANP derivatives, the potential application range encompasses virtually all DNA viruses. © 2015 Wiley Periodicals, Inc.


De Clercq E.,Rega Institute for Medical Research
Medicinal Research Reviews | Year: 2013

Prominent in the current stage of antiviral drug development are: (i) for human immunodeficiency virus (HIV), the use of fixed-dose combinations (FDCs), the most recent example being StribildTM; (ii) for hepatitis C virus (HCV), the pleiade of direct-acting antivirals (DAAs) that should be formulated in the most appropriate combinations so as to obtain a cure of the infection; (iii)-(v) new strategies (i.e., AIC316, AIC246, and FV-100) for the treatment of herpesvirus infections: herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), respectively; (vi) the role of a new tenofovir prodrug, tenofovir alafenamide (TAF) (GS-7340) for the treatment of HIV infections; (vii) the potential use of poxvirus inhibitors (CMX001 and ST-246); (viii) the usefulness of new influenza virus inhibitors (peramivir and laninamivir octanoate); (ix) the position of the hepatitis B virus (HBV) inhibitors [lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate (TDF)]; and (x) the potential of new compounds such as FGI-103, FGI-104, FGI-106, dUY11, and LJ-001 for the treatment of filoviruses (i.e., Ebola). Whereas for HIV and HCV therapy is aimed at multiple-drug combinations, for all other viruses, HSV, CMV, VZV, pox, influenza, HBV, and filoviruses, current strategies are based on the use of single compounds. © 2013 Wiley Periodicals, Inc.


De Clercq E.,Rega Institute for Medical Research
Medicinal Research Reviews | Year: 2013

The name of Antonín Holý has become synonymous for the era of acyclic nucleoside phosphonates (ANPs), which started with (S)-HPMPA as the prototype and (S)-HPMPC (cidofovir) as the first marketed compound. It has now evolved to a number of compounds clinically used in the treatment of HIV and hepatitis B virus infections, either as such [tenofovir disoproxil fumarate (TDF, Viread®)] or in combination [Truvada®, Atripla®, Complera®, Stribild®]. Truvada has also been approved for the prevention of HIV infections. Forthcoming is a new formulation of tenofovir (TAF: tenofovir alafenamide). Also forthcoming are several "quad" drug combinations containing either TDF or TAF. Other ANPs, based on either an alkoxy side chain or 5-azacytosine heterocycle seem highly promising and worth further pursuing. © 2013 Wiley Periodicals, Inc.


De Clercq E.,Rega Institute for Medical Research
Reviews in Medical Virology | Year: 2012

After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s). © 2012 John Wiley & Sons, Ltd.


Clercq E.D.,Rega Institute for Medical Research
Medicinal Research Reviews | Year: 2013

This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses. © 2012 Wiley Periodicals, Inc.


AMD3100 was originally discovered as an anti-HIV agent effective in inhibiting the replication of HIV in vitro at nanomolar concentrations. We found it to be a potent and selective antagonist of CXCR4, the receptor for the chemokine SDF-1 (now called CXCL12). AMD3100 was then developed, and marketed, as a stem cell mobilizer, and renamed plerixafor (Mozobil™). The path to the discovery of Mozobil™ as a stem cell mobilizer was described in Biochem. Pharmacol. 77: 1655-1664 (2009). Here I review the recent advances that have consolidated the role of plerixafor in mobilizing hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) from the bone marrow into the blood circulation. Plerixafor acts synergistically with granulocyte colony-stimulating factor (G-CSF), and its usefulness has been proven particularly for the mobilization of HSCs and HPCs for autologous stem cell transplantation in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). Plerixafor also has great potential for the treatment of hematological malignancies other than NHL and MM, and non-hematological malignancies, and, eventually, several other diseases depending on the CXCL12-CXCR4 interaction. Various AMD3100 analogs have been described (i.e. AMD11070, AMD3465, KRH-3955, T-140, and 4F-benzoyl-TN14003), primarily as potential anti-HIV agents. They are all strong CXCR4 antagonists. Their role in stem cell mobilization remains to be assessed. © 2010 Elsevier Inc.


De Clercq E.,Rega Institute for Medical Research
Biochemical Pharmacology | Year: 2014

The direct-acting antivirals (DAAs) currently in development for treatment of hepatitis C fall into four categories: (i) NS3/4A protease inhibitors: ABT-450/r, faldaprevir, asunaprevir, GS-9256, vedroprevir (GS-9451), danoprevir, MK-5172, vaniprevir, sovaprevir, ACH-2684, narlaprevir and simeprevir, in addition to those that are already developed [telaprevir (Incivek®) and boceprevir (Victrelis®)], (ii) NS5A protein inhibitors: ABT-267, daclatasvir, ledipasvir, ACH-2928, ACH-3102, PPI-668, AZD-7295, MK-8742, and GSK 2336805; (iii) NS5B (nucleoside-type) polymerase inhibitors: sofosbuvir (now approved by the FDA since 6 December 2013), GS-0938, mericitabine, VX-135, ALS 2158 and TMC 649128; (iv) NS5B (non-nucleoside-type) polymerase inhibitors: VX-222, ABT-072, ABT-333, deleobuvir, tegobuvir, setrobuvir, VCH-916, VCH-759, BMS-791325 and TMC-647055. Future drug combinations will likely exist of two or more DAAs belonging to any of the 4 categories, with the aim to achieve (i) pan-genotypic hepatitis C virus (HCV) activity, (ii) little or no risk for resistance; (iii) short duration (i.e. 12 weeks) of treatment, and (iv) a sustained viral response (SVR) and definite cure of the disease. © 2014 Elsevier Inc.


Cauwe B.,Rega Institute for Medical Research | Opdenakker G.,Rega Institute for Medical Research
Critical Reviews in Biochemistry and Molecular Biology | Year: 2010

Matrix metalloproteinases (MMPs), originally discovered to function in the breakdown of extracellular matrix proteins, have gained the status of regulatory proteases in signaling events by liganding and processing hormones, cytokines, chemokines, adhesion molecules and other membrane receptors. However, MMPs also cleave intracellular substrates and have been demonstrated within cells in nuclear, mitochondrial, various vesicular and cytoplasmic compartments, including the cytoskeletal intracellular matrix. Unbiased high-throughput degradomics approaches have demonstrated that many intracellular proteins are cleaved by MMPs, including apoptotic regulators, signal transducers, molecular chaperones, cytoskeletal proteins, systemic autoantigens, enzymes in carbohydrate metabolism and protein biosynthesis, transcriptional and translational regulators, and proteins in charge of protein clearance such as lysosomal and ubiquitination enzymes. Besides proteolysis inside cells, intracellular proteins may also be modulated by MMPs in the extracellular milieu. Indeed, many intracellular proteins exit cells by non-classical secretion mechanisms or by various conditions of cell death by apoptosis, necrosis and NETosis, and become accessible to extracellular proteases. Intracellular substrate proteolysis by MMPs is involved in innate immune defense and apoptosis, and affects oncogenesis and pathology of cardiac, neurological, protein conformational and autoimmune diseases, including ischemia-reperfusion injury, cardiomyopathy, Parkinson's disease, cataract, multiple sclerosis and systemic lupus erythematosus. Since the same MMP may affect physiology and pathology in different and even opposite ways, depending on its extracellular or subcellular localization, an additional layer of complexity is added to therapeutic MMP inhibition. Hence, further elucidation of intracellular MMP localizations and intracellular substrate proteolysis is a new challenge in MMP research. © 2010 Informa Healthcare USA, Inc.


De Clercq E.,Rega Institute for Medical Research
Biochemical Pharmacology | Year: 2013

Vaccination is possible to prevent infections with some viruses: hepatitis B virus (HBV), varicella-zoster virus (VZV), influenza A and B viruses, Yellow fever virus and poliovirus; but not for others: human immunodeficiency virus (HIV), hepatitis C virus (HCV), herpes simplex virus (HSV), cytomegalovirus (CMV), and most hemorrhagic fever viruses (HFV) (except for Yellow fever virus). Antiviral therapy is obviously needed to control those infections that are not amenable to prophylaxis by vaccination, but is also highly desirable for those infections where vaccination has not been implemented or did not fulfill its premises for complete protection. © 2013 Elsevier Inc.

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