TL;DR: The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
Abstract: The WHO recognizes human African trypanosomiasis, Chagas disease and the leishmaniases as neglected tropical diseases. These diseases are caused by parasitic trypanosomatids and range in severity from mild and self-curing to near invariably fatal. Public health advances have substantially decreased the effect of these diseases in recent decades but alone will not eliminate them. In this Review, we discuss why new drugs against trypanosomatids are required, approaches that are under investigation to develop new drugs and why the drug discovery pipeline remains essentially unfilled. In addition, we consider the important challenges to drug discovery strategies and the new technologies that can address them. The combination of new drugs, new technologies and public health initiatives is essential for the management, and hopefully eventual elimination, of trypanosomatid diseases from the human population.
TL;DR: Some of the challenges involved in developing new drugs to treatfectious tropical diseases are discussed, and there is still a long way to go.
Abstract: Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries These diseases predominantly affect the world's poorest people Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress While there have been notable successes, there is still a long way to go
145 citations
Cites background from "Anti-trypanosomatid drug discovery:..."
...This area has recently been reviewed in detail 60 ....
TL;DR: An optimized genome-scale gain-of-function library in trypanosomes was developed and used to identify the benzoxaborole target and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal Benzoxaboroles.
Abstract: African trypanosomes cause lethal and neglected tropical diseases, known as sleeping sickness in humans and nagana in animals Current therapies are limited, but fortunately, promising therapies are in advanced clinical and veterinary development, including acoziborole (AN5568 or SCYX-7158) and AN11736, respectively These benzoxaboroles will likely be key to the World Health Organization’s target of disease control by 2030 Their mode of action was previously unknown We have developed a high-coverage overexpression library and use it here to explore drug mode of action in Trypanosoma brucei Initially, an inhibitor with a known target was used to select for drug resistance and to test massive parallel library screening and genome-wide mapping; this effectively identified the known target and validated the approach Subsequently, the overexpression screening approach was used to identify the target of the benzoxaboroles, Cleavage and Polyadenylation Specificity Factor 3 (CPSF3, Tb92741340) We validated the CPSF3 endonuclease as the target, using independent overexpression strains Knockdown provided genetic validation of CPSF3 as essential, and GFP tagging confirmed the expected nuclear localization Molecular docking and CRISPR-Cas9-based editing demonstrated how acoziborole can specifically block the active site and mRNA processing by parasite, but not host CPSF3 Thus, our findings provide both genetic and chemical validation for CPSF3 as an important drug target in trypanosomes and reveal inhibition of mRNA maturation as the mode of action of the trypanocidal benzoxaboroles Understanding the mechanism of action of benzoxaborole-based therapies can assist development of improved therapies, as well as the prediction and monitoring of resistance, if or when it arises
85 citations
Cites background from "Anti-trypanosomatid drug discovery:..."
...The closely related parasites that cause acute and chronic forms of the human disease in Eastern and Western Africa are Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, respectively (1)....
TL;DR: This review discusses not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.
Abstract: Tritryps diseases are devastating parasitic neglected infections caused by Leishmania spp., Trypanosoma cruzi and Trypanosoma brucei subspecies. Together, these parasites affect more than 30 million people worldwide and cause high mortality and morbidity. Leishmaniasis comprises a complex group of diseases with clinical manifestation ranging from cutaneous lesions to systemic visceral damage. Antimonials, the first-choice drugs used to treat leishmaniasis, lead to high toxicity and carry significant contraindications limiting its use. Drug-resistant parasite strains are also a matter for increasing concern, especially in areas with very limited resources. The current scenario calls for novel and/or improvement of existing therapeutics as key research priorities in the field. Although several studies have shown advances in drug discovery towards leishmaniasis in recent years, key knowledge gaps in drug discovery pipelines still need to be addressed. In this review we discuss not only scientific and non-scientific bottlenecks in drug development, but also the central role of public-private partnerships for a successful campaign for novel treatment options against this devastating disease.
84 citations
Cites background from "Anti-trypanosomatid drug discovery:..."
...When applied properly, it can play a central role in the drug discovery pipeline (Wyatt et al., 2011; Field et al., 2017)....
TL;DR: This link between melarsoprol and AQP2 illustrates how a drug transporter can improve drug selectivity but, at the same time, highlights the risk of resistance when the drug uptake mechanism is dispensable for parasite viability and virulence.
81 citations
Cites background from "Anti-trypanosomatid drug discovery:..."
...To conclude, insights into drug mode of action and resistance mechanisms facilitate drug discovery and development and the design of optimal (combination) therapies and dosing strategies [89]....
TL;DR: The ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.
Abstract: Neglected tropical diseases (NTDs) are closely related to poverty and affect over a billion people in developing countries. The unmet treatment needs cause high mortality and disability thereby imposing a huge burden with severe social and economic consequences. Although coordinated by the World Health Organization, various philanthropic organizations, national governments and the pharmaceutical industry have been making efforts in improving the situation, the control of NTDs is still inadequate and extremely difficult today. The lack of safe, effective and affordable medicines is a key contributing factor. This paper reviews the recent advances and some of the challenges that we are facing in the fight against NTDs. In recent years, a number of innovations have demonstrated propensity to promote drug discovery and development for NTDs. Implementation of multilateral collaborations leads to continued efforts and plays a crucial role in drug discovery. Proactive approaches and advanced technologies are urgently needed in drug innovation for NTDs. However, the control and elimination of NTDs remain a formidable task as it requires persistent international cooperation to make sustainable progresses for a long period of time. Some currently employed strategies were proposed and verified to be successful, which involve both mechanisms of ‘Push’ which aims at cutting the cost of research and development for industry and ‘Pull’ which aims at increasing market attractiveness. Coupled to this effort should be the exercise of shared responsibility globally to reduce risks, overcome obstacles and maximize benefits. Since NTDs are closely associated with poverty, it is absolutely essential that the stakeholders take concerted and long-term measures to meet multifaceted challenges by alleviating extreme poverty, strengthening social intervention, adapting climate changes, providing effective monitoring and ensuring timely delivery. The ongoing endeavor at the global scale will ultimately benefit the patients, the countries they are living and, hopefully, the manufacturers who provide new preventive, diagnostic and therapeutic products.
70 citations
Cites background from "Anti-trypanosomatid drug discovery:..."
...Cellular assays are representatives of certain in vivo situation and suitable to preliminary evaluation of pharmacokinetic and/or pharmacodynamic profiles [47]....
TL;DR: In this paper, a pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single-guide RNA (sgRNA) library was described.
Abstract: The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 system for genome editing has greatly expanded the toolbox for mammalian genetics, enabling the rapid generation of isogenic cell lines and mice with modified alleles. Here, we describe a pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single-guide RNA (sgRNA) library. sgRNA expression cassettes were stably integrated into the genome, which enabled a complex mutant pool to be tracked by massively parallel sequencing. We used a library containing 73,000 sgRNAs to generate knockout collections and performed screens in two human cell lines. A screen for resistance to the nucleotide analog 6-thioguanine identified all expected members of the DNA mismatch repair pathway, whereas another for the DNA topoisomerase II ( TOP2A ) poison etoposide identified TOP2A , as expected, and also cyclin-dependent kinase 6, CDK6. A negative selection screen for essential genes identified numerous gene sets corresponding to fundamental processes. Last, we show that sgRNA efficiency is associated with specific sequence motifs, enabling the prediction of more effective sgRNAs. Collectively, these results establish Cas9/sgRNA screens as a powerful tool for systematic genetic analysis in mammalian cells.
TL;DR: Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of production to biotechnology companies.
Abstract: Biopharmaceutical companies attempting to increase productivity through novel discovery technologies have fallen short of achieving the desired results. Repositioning existing drugs for new indications could deliver the productivity increases that the industry needs while shifting the locus of production to biotechnology companies. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing.
TL;DR: A pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single-guide RNA (sgRNA) library is described and it is shown that sgRNA efficiency is associated with specific sequence motifs, enabling the prediction of more effective sgRNAs.
Abstract: The bacterial CRISPR/Cas9 system for genome editing has greatly expanded the toolbox for mammalian genetics, enabling the rapid generation of isogenic cell lines and mice with modified alleles. Here, we describe a pooled, loss-of-function genetic screening approach suitable for both positive and negative selection that uses a genome-scale lentiviral single guide RNA (sgRNA) library. sgRNA expression cassettes were stably integrated into the genome, which enabled a complex mutant pool to be tracked by massively parallel sequencing. We used a library containing 73,000 sgRNAs to generate knockout collections and performed screens in two human cell lines. A screen for resistance to the nucleotide analog 6-thioguanine identified all expected members of the DNA mismatch repair pathway, while another for the DNA topoisomerase II (TOP2A) poison etoposide identified TOP2A, as expected, and also cyclin-dependent kinase 6, CDK6. A negative selection screen for essential genes identified numerous gene sets corresponding to fundamental processes. Finally, we show that sgRNA efficiency is associated with specific sequence motifs, enabling the prediction of more effective sgRNAs. Collectively, these results establish Cas9/ sgRNA screens as a powerful tool for systematic genetic analysis in mammalian cells.
TL;DR: It is postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
Abstract: Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
TL;DR: It is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.
Abstract: Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.