Recent Advances in Repositioning Non-Antibiotics against Tuberculosis and other Neglected Tropical Diseases
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
The drug discovery and development landscape for infectious diseases is constantly changing with research interests shifting away from traditional approaches. De novo drug discovery and development is an exhaustive, time-consuming and costly multi-stage process that is faced with high attrition rates largely due to poor pharmacokinetics, toxicity and lack of efficacy in human subjects (Cook et al. 2014, Duran-Frigola et al. 2017, Hughes et al. 2011). Given the complexities associated with de novo approaches, alternative strategies that capitalize on past investments of such processes are gaining traction (Nwaka and Hudson 2006, Sharma et al. 2017, Zheng et al. 2018). Drug repositioning or repurposing is one such strategy that seeks new purposes for marketed or abandoned drugs. Other closely related strategies include drug reprofiling or redirecting (Ma et al. 2013, Persaud-Sharma and Zhou 2012). These terms are often used interchangeably as there is no consensus on terminology.
HIV Integrase Inhibitors
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
People with AIDS have a weak immune system and thus are at an increased risk of developing infections, lymphoma, and other types of cancer. Thus, HIV is also known as an oncovirus. The most common types of AIDS-related cancers are Kaposi sarcoma and non-Hodgkin’s lymphoma. Other AIDS-related cancers include Hodgkin’s disease and cancers of the lung, mouth, cervix, and digestive system (Chow et al. 2009; Palefsky 2012). A study conducted by the International Collaboration on HIV and Cancer (2000) reported a sharp decline in the incidence of Kaposi sarcoma and non-Hodgkin lymphoma in HIV-infected people on HAART treatment. Anti-HIV drugs target multiple pathways in the life cycle of HIV and provide a large source of potential anticancer drugs. Several FDA-approved anti-HIV drugs are being considered for repositioning as anticancer agents; among them, HIV protease inhibitor drugs seem to be more promising (Chow et al. 2009, Oprea et al. 2011). Recently, two classes of HIV IN inhibitors were also studied for repositioning as anticancer agents (Oprea and Mestres 2012; Zeng et al. 2012). Development of new drugs is a lengthy and costly process. Drug repositioning (i.e., repurposing or finding a new use for an existing drug) has gained considerable attention (Collins 2011), and the use of computational methods has significantly helped in these efforts (Andronis et al. 2011; Keiser et al. 2009). The repositioning of an approved drug has financial and other benefits, such as knowledge of its toxicity profile, drug metabolism, pharmacokinetics, and drug interactions.
Development and Commercialization of Asiaticoside in Madagascar
Charles Wambebe in African Indigenous Medical Knowledge and Human Health, 2018
One relevant example of drug polypharmacology and drug repositioning is the plant-derived drug aspirin, often used as an analgesic to relieve minor pains or as an antipyretic to reduce fever, and also acts as an anti-inflammatory medication to treat rheumatoid arthritis, pericarditis, and Kawasaki diseases. Additionally, it has been used in the prevention of transient ischemic attacks, strokes, and heart attacks. Triterpenoids of C. asiatica are also a good example of drug polypharmacology and drug repositioning. First used as a wound healing drug, they became key compounds in the cosmetic industry (Loiseau and Mercier, 2000). It was speculated that “the origins of polypharmacology lie precisely at the heart of protein evolution” (Jalencas and Mestres, 2013), meaning that natural products preferentially target proteins, which are essential to an organism, because these are effective defense substances (Dancik et al., 2010). Polypharmacology thus reflects the mechanisms of adaptation of biological systems to increase the chances of survival in an adverse environment. As exemplified by C. asiatica, many medicinal plants have multipurpose applications. It is therefore worthwhile to investigate medicinal plants within the paradigm of polypharmacology. Serendipitous observations using reverse pharmacology may help in this approach. At the African Network for Drug and Diagnostic Innovation (ANDI) meeting in Nairobi in 2010, Bernard Munos said: “Innovation thrives from the interaction between innovators and users; the majority (59%) of drug innovation come not from drug companies, but from doctors trying to help patients for whom standard therapy had failed.”
Drugs and biologics receiving FDA orphan drug designation: an analysis of the most frequently designated products and their repositioning strategies
Published in Expert Opinion on Orphan Drugs, 2021
Kathleen L. Miller, Selma Kraft, Abraham Ipe, Lewis Fermaglich
To better understand the business models underpinning rare disease drug development, we also analyzed the repositioning strategies in these highly designated products. The term ”repositioning” was chosen for this analysis because it represented a wide variety of business models, outside of novel drug development. We defined repositioning using the broad definition described in Allarakhia (2013): Drug [repositioning] involves finding new indications for existing drugs or potential drug candidates. Drugs or candidates include those in clinical development whose mechanism of action is relevant to multiple diseases; drugs that have failed to demonstrate efficacy for a particular indication during phase II or III trials but have no major safety concerns; drugs that have been discontinued for commercial reasons; marketed drugs for which patents are close to expiry; and drug candidates from academic institutions and public sector laboratories not yet fully pursued.[19]
Genomic opportunities for drug repositioning in systemic seropositive rheumatic diseases
Published in Expert Review of Clinical Immunology, 2020
Desiré Casares-Marfil, Javier Martín, Marialbert Acosta-Herrera
Drug research is a time-consuming and expensive process, where the main objective is to assess the impact of a specific drug in one or more biological targets for the treatment of certain disease. However, from all drugs evaluated in clinical development every year, only 15% of them are approved or even considered safe [1]. In this respect, there are several limitations associated with drug discovery, such as the identification of a specific target as a relevant biomarker, adverse effects not previously identified in early stages of long-term treatments, and heterogeneity of patients and its implication in drug effectiveness; all these especially relevant in rheumatic diseases [2]. In light of these issues, drug repositioning emerges as a new field in the drug industry. Drug repositioning is defined as the identification of new applications for existing drugs that have already passed development phases and were previously indicated to treat other diseases. Thus, this method allows saving time and resources providing new applications to existing drugs with known safety profiles [3]. Traditionally, it has been centered on drug-based and disease-based approaches, focused on drugs and disease features, respectively. However, nowadays the signature-based strategy evaluates the transcriptomic profiles on the basis of drug or disease similarities, as mentioned in a recent review by Kingsmore and colleagues [4]. In this review, we will focus on genomic methodologies for drug repositioning in systemic seropositive rheumatic diseases from a disease-based perspective.
Halogen bonding in halocarbon-protein complexes and computational tools for rational drug design
Published in Expert Opinion on Drug Discovery, 2019
Paulo J. Costa, Rafael Nunes, Diogo Vila-Viçosa
An interesting report on the use of computational tools to guide experimental work in the context of halocarbon–protein interactions was published by Weiliang Zhu and co-workers [112] featuring their own XBScoreQM scoring function (Section 4) implemented in their D3DOCKxb software. The authors aimed at the efficient repositioning of organohalogen drugs, developing potent B-Raf protein kinase mutant V600E inhibitors via docking and bioassays. Notice that drug repositioning is quite advantageous given the reduced development cost and a lower probability of failure due to safety risks. A total of 1634 organohalogen drugs were retrieved from the Comprehensive Medicinal Chemistry database (CMC) and docked against two B-Raf structures, one complexed with sorafenib, 14 (PDB ID: 1UWJ), and the other with PLX4720, 15 (PDB ID: 3C4C). From these, 67 compounds whose score was higher than the crystallized inhibitor and whose binding poses showed the existence of halogen bonds were selected. Visual inspection of the results allowed the selection of three commercial drugs for experimental assays, namely rafoxanide, closantel, and cypermethrin. The first two drugs showed potent activity against B-Raf V600E (IC50 = 0.07μM and 1.90μM, respectively) while the latter was inactive.