Foreword Special Focus Issue: Schistosomiasis
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Future
Medicinal Chemistry
Schistosomiasis and its treatment “This special focus issue of Future Medicinal Chemistry is impressive for the breadth of contributor expertise in the field of schistosomiasis...” Keywords: drug development • drug resistance • medicinal chemistry • natural products • Open Source Discovery • praziquantel • Schistosomiasis • Schistosoma • tropical disease
Schistosomiasis is one of the number of chronic and morbid infectious ‘worm’ diseases of poverty that afflicts approximately the equivalent of the population of Brazil (∼200,000,000) with perhaps three-times that number at risk of infection. Caused by a trematode flatworm that is transmitted via freshwater snails, infections can last a lifetime (starting in children just a few months old) robbing individuals and families of full health, schooling and productivity, and leaving many in chronic and debilitating pain. Schistosomiasis is a serious burden on subsistence communities in endemic areas. Remarkably, for over 30 years, we have relied on just one drug, praziquantel (PZQ), to treat and control this disease. In the early 1970s, PZQ was synthesized among a series of pyrazino isoquinolines at E. Merck of Darmstadt in an attempt to identify tranquilizers. The series was passed onto Bayer AG of Leverkusen which, through the extensive use of animal models of various helminth infections, identified the potent anti-flatworm properties of PZQ. By 1978, PZQ had started trials in humans as an anti-schistosomal drug candidate and was soon on the market as Biltricide® for use in humans [1] . In 1983, Shin Poong of South Korea produced PZQ under a new synthesis patent and the drug’s price dropped to a point where mass treatments could be entertained. As ivermectin is for nematode infections, PZQ continues to be the ‘wonder drug’ for schistosomiasis and many other flatworm infections by providing safe and effective oral treatment that has dramatically decreased disease prevalence and morbidity.
10.4155/FMC.15.27 © 2015 Future Science Ltd
Resistance (?) & the need for new drugs After PZQ, neither the pharmaceutical industry nor international donor agencies thought too much more about the possible need for alternative drugs for schistosomiasis. Some would say that we do not need a new drug – after years of sometimes intense use (e.g., in Egypt [2]), we have yet to see clinically relevant resistance to PZQ emerge. However, with the recent and serious upsurge in philanthropic, international agency and government support for increased production and distribution of PZQ [3,4] , this comfortable situation may be in danger of being eroded. We should prepare in case meaningful resistance develops to this most valuable of drugs. Irrespective of the ‘the specter’ of drug resistance, it is also important to consider PZQ’s principal drawbacks as a drug. These are: decreased or a complete lack of activity against younger parasite stages relative to mature worms, meaning that immature parasites survive drug exposure and go on to produce morbidity; the racemic nature of PZQ, meaning that half of the dose is pharmacologically useless, thereby contributing to the unnecessarily large 600 mg tablet and final dose of 40 mg/kg (by comparison albendazole for treatment of roundworms is around 7 mg/kg); and rapid metabolism (via hydroxylation) of the absorbed drug to inactive metabolites such that very little drug comes into contact with the worm in the blood circulation [5] . Finally, it is worth remembering that PZQ is recommended for humans as three fractional
Future Med. Chem. (2015) 7(6), 675–676
Conor R Caffrey Center for Discovery & Innovation in Parasitic Diseases, Department of Pathology, University of California, San Francisco, CA 94158, USA [email protected]
part of
ISSN 1756-8919
675
Foreword Caffrey doses of 20 mg/kg each in one day. By contrast, mass deworming campaigns employ a single 40 mg/kg dose. As a result, although worm burdens are decreased in the range of 60–90% [6,7] , complete cure is not reliably achieved. Obviously, from the standpoints of both the patient and the continued transmission of the parasite into the environment, this lack of parasite clearance is not ideal for mass administration of a single-dose drug. Bearing in mind these concerns and given the new resources, tools and community energy exemplified below, as well as the renewed attention to infectious (‘neglected’) diseases of poverty in general over the last 15 years, we can and should be looking for alternative drugs. What this issue offers This special focus issue of Future Medicinal Chemistry is impressive for the breadth of contributor expertise in the field of schistosomiasis; from leaders directly involved in disease surveillance and PZQ distribution programs to key research innovators and facilitators working in academia, industry and non-governmental organizations. It is abundantly clear from the articles herein that the drug discovery process for this disease has matured from the ‘traditional,’ often serendipitous, screening of compounds against parasites in culture or in animal infection models (although where would PZQ be without such?) to include many of the other ‘modern’ disciplines (e.g., molecular modeling, target-based screening, mechanism of action studies and medicinal chemistry) that enrich the opportunities for identifying and moving forward valuable chemistries. Key to these advances has been the increasing accessibility of comprehensive (epi)genomic and transcriptomic data with which targetbased approaches can be seriously entertained. In addition to articles disclosing various synthetic chemistry approaches, natural products are also featured. These will be a fundamental source of new chemical entities in the future, facilitated by the fact that many References 1
Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel. Med. Res. Rev. 3, 147–200 (1983).
2
Fenwick A, Savioli L, Engels D, Bergquist NR, Todd MH. Drugs for the control of parasitic diseases: current status and development in schistosomiasis. Trends Parasitol. 19, 509–515 (2003).
3
4
676
World Health Organization. Accelerating work to overcome the global impact of neglected tropical diseases – a roadmap for implementation. World health Organization, Geneva, Switzerland (2012). www.who.int/neglected_diseases Uniting to combat neglected tropical diseases. http://unitingtocombatntds.org
Future Med. Chem. (2015) 7(6)
of the countries producing the incredible chemical diversity are also endemic for this and other diseases of poverty. Also given prominence is Open Source Discovery, an area that has been of recent relevance to schistosomiasis whereby organic, medicinal and process chemists came together online to solve the vexing question of how to produce the active enantiomer of PZQ at scale [8,9] , which is surely a major advance for disease control. Finally, the special focus issue includes timely discussions on the new and expanding collaborations within academia and between industry and academia, thanks in part to the community-level activities of entities such as BIO Ventures for Global Health and WIPO Re:Search. These discussions also address how to identify and best manage intellectual property, not least among academics, for whom the first impulse to publish may not necessarily be the most beneficial if exciting new anti-parasitics are to realize their full potential. Overall, the topics covered here communicate not just the excellence and breadth of the drug discovery research being undertaken but also the spirit of cooperation, dynamism and ‘can-do’ attitude in a field that has languished somewhat in attention relative to other infectious diseases of poverty. I am very grateful to the contributors for their time and expertise, and finally, our collective thanks to the Future Medicinal Chemistry team for making this special focus issue available online without charge. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 5
Bühring KU, Diekmann HW, Müller H, Garbe A, Nowak H. Metabolism of praziquantel in man. Eur. J. Drug Metab. Pharm. 3, 179–190 (1978).
6
Wegner DHG. The profile of the trematodicidal compound praziquantel. Arzneimittelforschung 34, 1132–1136 (1984).
7
Black CL, Steinauer ML, Mwinzi PN, Secor WE, Karanja DM, Colley DG. Impact of intense, longitudinal retreatment with praziquantel on cure rates of schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya. Trop. Med. Int. Health. 14, 450–457 (2009).
8
Woelfle M, Olliaro P, Todd MH. Open science is a research accelerator. Nat. Chem. 3, 745–748 (2011).
9
Woelfle M, Seerden JP, de Gooijer J, Pouwer K, Olliaro P, Todd MH. Resolution of praziquantel. PLoS Negl. Trop. Dis. 5, e1260 (2011).
future science group
For reprint orders, please contact [email protected]
Future
Medicinal Chemistry
Schistosomiasis and its treatment “This special focus issue of Future Medicinal Chemistry is impressive for the breadth of contributor expertise in the field of schistosomiasis...” Keywords: drug development • drug resistance • medicinal chemistry • natural products • Open Source Discovery • praziquantel • Schistosomiasis • Schistosoma • tropical disease
Schistosomiasis is one of the number of chronic and morbid infectious ‘worm’ diseases of poverty that afflicts approximately the equivalent of the population of Brazil (∼200,000,000) with perhaps three-times that number at risk of infection. Caused by a trematode flatworm that is transmitted via freshwater snails, infections can last a lifetime (starting in children just a few months old) robbing individuals and families of full health, schooling and productivity, and leaving many in chronic and debilitating pain. Schistosomiasis is a serious burden on subsistence communities in endemic areas. Remarkably, for over 30 years, we have relied on just one drug, praziquantel (PZQ), to treat and control this disease. In the early 1970s, PZQ was synthesized among a series of pyrazino isoquinolines at E. Merck of Darmstadt in an attempt to identify tranquilizers. The series was passed onto Bayer AG of Leverkusen which, through the extensive use of animal models of various helminth infections, identified the potent anti-flatworm properties of PZQ. By 1978, PZQ had started trials in humans as an anti-schistosomal drug candidate and was soon on the market as Biltricide® for use in humans [1] . In 1983, Shin Poong of South Korea produced PZQ under a new synthesis patent and the drug’s price dropped to a point where mass treatments could be entertained. As ivermectin is for nematode infections, PZQ continues to be the ‘wonder drug’ for schistosomiasis and many other flatworm infections by providing safe and effective oral treatment that has dramatically decreased disease prevalence and morbidity.
10.4155/FMC.15.27 © 2015 Future Science Ltd
Resistance (?) & the need for new drugs After PZQ, neither the pharmaceutical industry nor international donor agencies thought too much more about the possible need for alternative drugs for schistosomiasis. Some would say that we do not need a new drug – after years of sometimes intense use (e.g., in Egypt [2]), we have yet to see clinically relevant resistance to PZQ emerge. However, with the recent and serious upsurge in philanthropic, international agency and government support for increased production and distribution of PZQ [3,4] , this comfortable situation may be in danger of being eroded. We should prepare in case meaningful resistance develops to this most valuable of drugs. Irrespective of the ‘the specter’ of drug resistance, it is also important to consider PZQ’s principal drawbacks as a drug. These are: decreased or a complete lack of activity against younger parasite stages relative to mature worms, meaning that immature parasites survive drug exposure and go on to produce morbidity; the racemic nature of PZQ, meaning that half of the dose is pharmacologically useless, thereby contributing to the unnecessarily large 600 mg tablet and final dose of 40 mg/kg (by comparison albendazole for treatment of roundworms is around 7 mg/kg); and rapid metabolism (via hydroxylation) of the absorbed drug to inactive metabolites such that very little drug comes into contact with the worm in the blood circulation [5] . Finally, it is worth remembering that PZQ is recommended for humans as three fractional
Future Med. Chem. (2015) 7(6), 675–676
Conor R Caffrey Center for Discovery & Innovation in Parasitic Diseases, Department of Pathology, University of California, San Francisco, CA 94158, USA [email protected]
part of
ISSN 1756-8919
675
Foreword Caffrey doses of 20 mg/kg each in one day. By contrast, mass deworming campaigns employ a single 40 mg/kg dose. As a result, although worm burdens are decreased in the range of 60–90% [6,7] , complete cure is not reliably achieved. Obviously, from the standpoints of both the patient and the continued transmission of the parasite into the environment, this lack of parasite clearance is not ideal for mass administration of a single-dose drug. Bearing in mind these concerns and given the new resources, tools and community energy exemplified below, as well as the renewed attention to infectious (‘neglected’) diseases of poverty in general over the last 15 years, we can and should be looking for alternative drugs. What this issue offers This special focus issue of Future Medicinal Chemistry is impressive for the breadth of contributor expertise in the field of schistosomiasis; from leaders directly involved in disease surveillance and PZQ distribution programs to key research innovators and facilitators working in academia, industry and non-governmental organizations. It is abundantly clear from the articles herein that the drug discovery process for this disease has matured from the ‘traditional,’ often serendipitous, screening of compounds against parasites in culture or in animal infection models (although where would PZQ be without such?) to include many of the other ‘modern’ disciplines (e.g., molecular modeling, target-based screening, mechanism of action studies and medicinal chemistry) that enrich the opportunities for identifying and moving forward valuable chemistries. Key to these advances has been the increasing accessibility of comprehensive (epi)genomic and transcriptomic data with which targetbased approaches can be seriously entertained. In addition to articles disclosing various synthetic chemistry approaches, natural products are also featured. These will be a fundamental source of new chemical entities in the future, facilitated by the fact that many References 1
Andrews P, Thomas H, Pohlke R, Seubert J. Praziquantel. Med. Res. Rev. 3, 147–200 (1983).
2
Fenwick A, Savioli L, Engels D, Bergquist NR, Todd MH. Drugs for the control of parasitic diseases: current status and development in schistosomiasis. Trends Parasitol. 19, 509–515 (2003).
3
4
676
World Health Organization. Accelerating work to overcome the global impact of neglected tropical diseases – a roadmap for implementation. World health Organization, Geneva, Switzerland (2012). www.who.int/neglected_diseases Uniting to combat neglected tropical diseases. http://unitingtocombatntds.org
Future Med. Chem. (2015) 7(6)
of the countries producing the incredible chemical diversity are also endemic for this and other diseases of poverty. Also given prominence is Open Source Discovery, an area that has been of recent relevance to schistosomiasis whereby organic, medicinal and process chemists came together online to solve the vexing question of how to produce the active enantiomer of PZQ at scale [8,9] , which is surely a major advance for disease control. Finally, the special focus issue includes timely discussions on the new and expanding collaborations within academia and between industry and academia, thanks in part to the community-level activities of entities such as BIO Ventures for Global Health and WIPO Re:Search. These discussions also address how to identify and best manage intellectual property, not least among academics, for whom the first impulse to publish may not necessarily be the most beneficial if exciting new anti-parasitics are to realize their full potential. Overall, the topics covered here communicate not just the excellence and breadth of the drug discovery research being undertaken but also the spirit of cooperation, dynamism and ‘can-do’ attitude in a field that has languished somewhat in attention relative to other infectious diseases of poverty. I am very grateful to the contributors for their time and expertise, and finally, our collective thanks to the Future Medicinal Chemistry team for making this special focus issue available online without charge. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. 5
Bühring KU, Diekmann HW, Müller H, Garbe A, Nowak H. Metabolism of praziquantel in man. Eur. J. Drug Metab. Pharm. 3, 179–190 (1978).
6
Wegner DHG. The profile of the trematodicidal compound praziquantel. Arzneimittelforschung 34, 1132–1136 (1984).
7
Black CL, Steinauer ML, Mwinzi PN, Secor WE, Karanja DM, Colley DG. Impact of intense, longitudinal retreatment with praziquantel on cure rates of schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya. Trop. Med. Int. Health. 14, 450–457 (2009).
8
Woelfle M, Olliaro P, Todd MH. Open science is a research accelerator. Nat. Chem. 3, 745–748 (2011).
9
Woelfle M, Seerden JP, de Gooijer J, Pouwer K, Olliaro P, Todd MH. Resolution of praziquantel. PLoS Negl. Trop. Dis. 5, e1260 (2011).
future science group
