Generic placeholder image

Current Drug Discovery Technologies

Author(s): Martin Braddock*

DOI: 10.2174/1570163816666190112150014

DownloadDownload PDF Flyer Cite As
From Target Identification to Drug Development in Space: Using the Microgravity Assist

Page: [45 - 56] Pages: 12

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

The unique nature of microgravity encountered in space provides an opportunity for drug discovery and development that cannot be replicated on Earth. From the production of superior protein crystals to the identification and validation of new drug targets to microarray analyses of transcripts attenuated by microgravity, there are numerous examples which demonstrate the benefit of exploiting the space environment. Moreover, studies conducted on Space Shuttle missions, the International Space Station and other craft have had a direct benefit for drug development programmes such as those directed against reducing bone and muscle loss or increasing bone formation. This review will highlight advances made in both drug discovery and development and offer some future insight into how drug discovery and associated technologies may be further advanced using the microgravity assist.

Keywords: Microgravity, target identification, target validation, drug development, protein crystallization, protein crystals.

Graphical Abstract

[1]
Aubert AE, Larina I, Momken I, et al. Towards human exploration of space: The THESEUS review series on cardiovascular, respiratory, and renal research priorities. NPJ Microgravity 2016; 2: 16031.
[http://dx.doi.org/10.1038/npjmgrav.2016.31] [PMID: 28725739]
[2]
Caiani EG, Martin-Yebra A. Weightlessness and cardiac rhythm disorders: Current knowledge from space flight and bed-rest studies. Front Astron Space Sci 2016; 3: 1-6.
[http://dx.doi.org/10.3389/fspas.2016.00027]
[3]
Carpenter RD, Lang TF, Bloomfield SA, et al. Effects of long-duration spaceflight, microgravity and radiation on the neuromuscular, sensorimotor and skeletal systems. J Cosmol 2010; 12: 3778-80.
[4]
Cavanagh PR, Licata AA, Rice AJ. Exercise and pharmacological countermeasures for bone loss during long-duration space flight. Gravit Space Biol Bull 2005; 18(2): 39-58.
[PMID: 16038092]
[5]
Graebe A, Schuck EL, Lensing P, Putcha L, Derendorf H. Physiological, pharmacokinetic, and pharmacodynamic changes in space. J Clin Pharmacol 2004; 44(8): 837-53.
[http://dx.doi.org/10.1177/0091270004267193] [PMID: 15286087]
[6]
Lang T, Van Loon JJWA, Bloomfield S, et al. Towards human exploration of space: The THESEUS review series on muscle and bone research priorities. NPJ Microgravity 2017; 3: 8.
[http://dx.doi.org/10.1038/s41526-017-0013-0] [PMID: 28649630]
[7]
Van Ombergen A, Demertzi A, Tomilovskaya E, et al. The effect of spaceflight and microgravity on the human brain. J Neurol 2017; 264(Suppl. 1): 18-22.
[http://dx.doi.org/10.1007/s00415-017-8427-x] [PMID: 28271409]
[8]
Braddock M. Ergonomic challenges for astronauts during space travel and the need for space medicine. J Ergonomics 2017; 7: 1-10.
[http://dx.doi.org/10.4172/2165-7556.1000221]
[9]
Clément G. International roadmap for artificial gravity research. NPJ Microgravity 2017; 3: 29.
[http://dx.doi.org/10.1038/s41526-017-0034-8] [PMID: 29184903]
[10]
Zea L. Drug Discovery and development in space, IAC-15- A1.8x27627 66th International Astronautical Congress. Jerusalem, Israel. October 12-16, 2015;
[11]
Astronaut/cosmonaut statistics retrieved on October 11th 2018 https://www.worldspaceflight.com/bios/stats.php
[12]
Crucian B, Sams C. Immune system dysregulation during spaceflight: clinical risk for exploration-class missions. J Leukoc Biol 2009; 86(5): 1017-8.
[http://dx.doi.org/10.1189/jlb.0709500] [PMID: 19875627]
[13]
Crucian B, Simpson RJ, Mehta S, et al. Terrestrial stress analogs for spaceflight associated immune system dysregulation. Brain Behav Immun 2014; 39: 23-32.
[http://dx.doi.org/10.1016/j.bbi.2014.01.011] [PMID: 24462949]
[14]
Crucian B, Babiak-Vazquez A, Johnston S, Pierson DL, Ott CM, Sams C. Incidence of clinical symptoms during long-duration orbital spaceflight. Int J Gen Med 2016; 9: 383-91.
[http://dx.doi.org/10.2147/IJGM.S114188] [PMID: 27843335]
[15]
Huin-Schohn C, Guéguinou N, Schenten V, et al. Gravity changes during animal development affect IgM heavy-chain transcription and probably lymphopoiesis. FASEB J 2013; 27(1): 333-41.
[http://dx.doi.org/10.1096/fj.12-217547] [PMID: 22993194]
[16]
Sonnenfeld G. The immune system in space and microgravity. Med Sci Sports Exerc 2002; 34(12): 2021-7.
[http://dx.doi.org/10.1097/00005768-200212000-00024] [PMID: 12471311]
[17]
Mader TH, Gibson CR, Pass AF, et al. Optic disc edema, globe flattening, choroidal folds, and hyperopic shifts observed in astronauts after long-duration space flight. Ophthalmology 2011; 118(10): 2058-69.
[http://dx.doi.org/10.1016/j.ophtha.2011.06.021] [PMID: 21849212]
[18]
Mader TH, Gibson CR, Pass AF, et al. Optic disc edema in an astronaut after repeat long-duration space flight. J Neuroophthalmol 2013; 33(3): 249-55.
[http://dx.doi.org/10.1097/WNO.0b013e31829b41a6] [PMID: 23851997]
[19]
Mader TH, Gibson CR, Otto CA, et al. Persistent asymmetric optic disc swelling after long-duration space flight: Implications for pathogenesis. J Neuroophthalmol 2017; 37(2): 133-9.
[http://dx.doi.org/10.1097/WNO.0000000000000467] [PMID: 27930421]
[20]
Taibbi G, Cromwell RL, Kapoor KG, Godley BF, Vizzeri G. The effect of microgravity on ocular structures and visual function: A review. Surv Ophthalmol 2013; 58(2): 155-63.
[http://dx.doi.org/10.1016/j.survophthal.2012.04.002] [PMID: 23369516]
[21]
DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs. J Health Econ 2016; 47: 20-33.
[http://dx.doi.org/10.1016/j.jhealeco.2016.01.012] [PMID: 26928437]
[22]
Khanna I. Drug discovery in pharmaceutical industry: Productivity challenges and trends. Drug Discov Today 2012; 17(19-20): 1088-102.
[http://dx.doi.org/10.1016/j.drudis.2012.05.007] [PMID: 22627006]
[23]
Schuhmacher A, Gassmann O, Hinder M, Changing R . Changing R & D models in research-based pharmaceutical companies. J Transl Med 2016; 14(1): 105.
[http://dx.doi.org/10.1186/s12967-016-0838-4] [PMID: 27118048]
[24]
Paul SM, Mytelka DS, Dunwiddie CT, et al. How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 2010; 9(3): 203-14.
[http://dx.doi.org/10.1038/nrd3078] [PMID: 20168317]
[25]
Scannell JW, Blanckley A, Boldon H, Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov 2012; 11(3): 191-200.
[http://dx.doi.org/10.1038/nrd3681] [PMID: 22378269]
[26]
Terry C. A new future for R&D? Measuring the return from pharmaceutical innovation In: Terry C, Lesser N Deloitte. Global Date 2017. Deloitte retrieved on September 25th https: //www2.deloitte.com/us/en/pages/life-sciences-and-health-care/articles/measuring-return-from-pharmaceutical-innovation.html
[27]
Tufts center for the study of drug development retrieved on October 2nd https://csdd.tufts.edu/
[28]
Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery. Br J Pharmacol 2011; 162(6): 1239-49.
[http://dx.doi.org/10.1111/j.1476-5381.2010.01127.x] [PMID: 21091654]
[29]
Marsden CJ, Eckersley S, Hebditch M, et al. The use of antibodies in small-molecule drug discovery. J Biomol Screen 2014; 19(6): 829-38.
[http://dx.doi.org/10.1177/1087057114527770] [PMID: 24695620]
[30]
Perez HL, Cardarelli PM, Deshpande S, et al. Antibody-drug conjugates: Current status and future directions. Drug Discov Today 2014; 19(7): 869-81.
[http://dx.doi.org/10.1016/j.drudis.2013.11.004] [PMID: 24239727]
[31]
Valeur E, Jimonet P. New modalities, technologies and partnerships in probe and lead generation: Enabling a mode-of-action centric paradigm. J Med Chem 2018; 61(20): 9004-29.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00378] [PMID: 29851477]
[32]
Valeur E, Guéret SM, Adihou H, et al. New modalities for challenging targets in drug discovery. Angew Chem Int Ed Engl 2017; 56(35): 10294-323.
[http://dx.doi.org/10.1002/anie.201611914] [PMID: 28186380]
[33]
Monte AA, Brocker C, Nebert DW, Gonzalez FJ, Thompson DC, Vasiliou V. Improved drug therapy: Triangulating phenomics with genomics and metabolomics. Hum Genomics 2014; 8: 16.
[http://dx.doi.org/10.1186/s40246-014-0016-9] [PMID: 25181945]
[34]
Cook D, Brown D, Alexander R, et al. Lessons learned from the fate of AstraZeneca’s drug pipeline: A five-dimensional framework. Nat Rev Drug Discov 2014; 13(6): 419-31.
[http://dx.doi.org/10.1038/nrd4309] [PMID: 24833294]
[35]
Morgan P, Brown DG, Lennard S, et al. Impact of a five-dimensional framework on R&D productivity at AstraZeneca. Nat Rev Drug Discov 2018; 17(3): 167-81.
[http://dx.doi.org/10.1038/nrd.2017.244] [PMID: 29348681]
[36]
Experiments by Hardware - 100418 retrieved on October 9th https://www.nasa.gov/mission_pages/station/research/experiments/experiments_hardware.html
[37]
Experiment List - Alphabetical - 100418 retrieved on Octo-ber 9th 2018 https://www.nasa.gov/mission_pages/station/research/experiments/experiments_by_name.html
[38]
GeneLab open science for life in space retrieved on October 9th 2018 https://genelab.nasa.gov/
[39]
Beheshti A, Ray S, Fogle H, Berrios D, Costes SV. A microRNA signature and TGF-β1 response were identified as the key master regulators for spaceflight response. PLoS One 2018; 13(7) e0199621
[http://dx.doi.org/10.1371/journal.pone.0199621] [PMID: 30044882]
[40]
Meng X-M, Nikolic-Paterson DJ, Lan HY. TGF-β: The master regulator of fibrosis. Nat Rev Nephrol 2016; 12(6): 325-38.
[http://dx.doi.org/10.1038/nrneph.2016.48] [PMID: 27108839]
[41]
Morrison MD, Nicholson WL. Meta-analysis of data from spaceflight transcriptome experiments does not support the idea of a common bacterial “spaceflight response”. Sci Rep 2018; 8(1): 14403.
[http://dx.doi.org/10.1038/s41598-018-32818-z] [PMID: 30258082]
[42]
Kamal KY, Herranz R, van Loon JJWA, Medina FJ. Simulated microgravity, Mars gravity, and 2g hypergravity affect cell cycle regulation, ribosome biogenesis, and epigenetics in Arabidopsis cell cultures. Sci Rep 2018; 8(1): 6424.
[http://dx.doi.org/10.1038/s41598-018-24942-7] [PMID: 29686401]
[43]
Thiel CS, Tauber S, Christoffel S, et al. Rapid coupling between gravitational forces and the transcriptome in human myelomonocytic U937 cells. Sci Rep 2018; 8(1): 13267.
[http://dx.doi.org/10.1038/s41598-018-31596-y] [PMID: 30185876]
[44]
Zheng H, Hou J, Zimmerman MD, Wlodawer A, Minor W. The future of crystallography in drug discovery. Expert Opin Drug Discov 2014; 9(2): 125-37.
[http://dx.doi.org/10.1517/17460441.2014.872623] [PMID: 24372145]
[45]
Long MM, DeLucas LJ, Smith C, et al. Protein crystal growth in microgravity-temperature induced large scale crystallization of insulin. Microgravity Sci Technol 1994; 7(2): 196-202.
[PMID: 11541852]
[46]
Reichert P, Nagabhushan TL, Long MM, et al. Macroscale production and analysis of crystalline interferon a-2B in microgravity on STS-52. Proceedings of Symposium on NASA Centers for the Commercial Development of Space. Albuquerque, New Mexico. January 7-10, 1996;
[47]
Habash J, Boggon TJ, Raftery J, Chayen NE, Zagalsky PF, Helliwell JR. Apocrustacyanin C(1) crystals grown in space and on earth using vapour-diffusion geometry: Protein structure refinements and electron-density map comparisons. Acta Crystallogr D Biol Crystallogr 2003; 59(Pt 7): 1117-23.
[http://dx.doi.org/10.1107/S0907444903007959] [PMID: 12832753]
[48]
DeLucas LJ, Moore KM, Long MM. Protein crystal growth and the International Space Station. Gravit Space Biol Bull 1999; 12(2): 39-45.
[PMID: 11541781]
[49]
DeLucas LJ. Protein crystallization - is it rocket science? Drug Discov Today 2001; 6(14): 734-44.
[http://dx.doi.org/10.1016/S1359-6446(01)01838-4] [PMID: 11445465]
[50]
McPherson A, DeLucas LJ. Microgravity protein crystallization. NPJ Microgravity 2015; 1: 15010.
[http://dx.doi.org/10.1038/npjmgrav.2015.10] [PMID: 28725714]
[51]
Betzel C, Martirosyan A, Ruyters G. Protein crystallization on the International Space Station ISS pp27-39 Biotechnology in Space Springer Briefs in Space Life Sciences Springer Publishers. 2017.
[52]
Strelov VI, Kuranova IP, Zakharov BG, et al. Crystallization in space: Results and prospects. Crystallogr Rep 2014; 59: 781-806.
[http://dx.doi.org/10.1134/S1063774514060285]
[53]
Vonortas NS. Protein crystallization for drug development: A prospective empirical appraisal of economic effects of ISS microgravity 2015. NASA final report.
[54]
Space protein crystallization documents retrieved on October 9th https://sites.google.com/site/spaceproteincrystalization/spaceproteincrystallizationdocuments
[55]
The effect of microgravity on the co-crystallization of a mem-brane protein with a medically relevant compound.. (CASIS PCG 4-2) - 021418 retrieved on October 9th https: //www. nasa.gov/mission_pages/station/research/experiments/2346.html
[56]
NanoRacks-Protein crystal growth in microgravity to enable therapeutic discovery (NanoRacks-PCG Therapeutic Discov-ery) - 07.19.. 18retrieved on October 9th 2018 https://www.nasa.gov/mission_pages/station/research/experiments/1957.html
[57]
NASA technical reports server: (PCG) Protein crystal growth HIV reversetranscriptase retrieved on October 9th 2018 https: //ntrs.nasa.gov/search.jsp?R=MSFC-9262301&hterms=reverse+transcriptase&qs=N%3D0%26Ntk%3DAll%26Ntt%3Dreverse%2520transcriptase%26Ntx%3Dmode%2520matchallpartial
[58]
Williamson-Smith A Reshaping drug deliver: millions of crys-tals at a timeretrieved on October 9th 2018 https://upward.iss-casis.org/millions-of-crystals-at-a-time/
[59]
Chayen NE. Microgravity protein crystallization aboard the photon satellite. J Cryst Growth 1995; 153: 175-9.
[http://dx.doi.org/10.1016/0022-0248(95)00188-3]
[60]
Mathea S, Baptista M, Reichert P, et al. Crystallizing the Parkinson’s disease protein LRRK2 under microgravity conditions. bioRxiv 2018. [Epub ahead of print].
[61]
Chatani M, Morimoto H, Takeyama K, et al. Acute transcriptional up-regulation specific to osteoblasts/osteoclasts in Medaka Fish immediately after exposure to microgravity. Sci Rep 2016; 6: 39545.
[http://dx.doi.org/10.1038/srep39545] [PMID: 28004797]
[62]
Blaber EA, Dvorochkin N, Lee C, et al. Microgravity induces pelvic bone loss through osteoclastic activity, osteocytic osteolysis, and osteoblastic cell cycle inhibition by CDKN1a/p21. PLoS One 2013; 8(4) e61372
[http://dx.doi.org/10.1371/journal.pone.0061372] [PMID: 23637819]
[63]
Leblanc A, Matsumoto T, Jones J, et al. Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight. Osteoporos Int 2013; 24(7): 2105-14.
[http://dx.doi.org/10.1007/s00198-012-2243-z] [PMID: 23334732]
[64]
Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of low bone density or osteoporosis to prevent fractures in men and women: A clinical practice guideline update from the American College of Physicians. Ann Intern Med 2017; 166(11): 818-39.
[http://dx.doi.org/10.7326/M15-1361] [PMID: 28492856]
[65]
Lacey DL, Tan HL, Lu J, et al. Osteoprotegerin ligand modulates murine osteoclast survival in vitro and in vivo. Am J Pathol 2000; 157(2): 435-48.
[http://dx.doi.org/10.1016/S0002-9440(10)64556-7] [PMID: 10934148]
[66]
Ominsky MS, Boyce RW, Li X, Ke HZ. Effects of sclerostin antibodies in animal models of osteoporosis. Bone 2017; 96: 63-75.
[http://dx.doi.org/10.1016/j.bone.2016.10.019] [PMID: 27789417]
[67]
Puolakkainen T, Ma H, Kainulainen H, et al. Treatment with soluble activin type IIB-receptor improves bone mass and strength in a mouse model of Duchenne muscular dystrophy. BMC Musculoskelet Disord 2017; 18(1): 20.
[http://dx.doi.org/10.1186/s12891-016-1366-3] [PMID: 28103859]
[68]
Lloyd SA, Morony SE, Ferguson VL, et al. Osteoprotegerin is an effective countermeasure for spaceflight-induced bone loss in mice. Bone 2015; 81: 562-72.
[http://dx.doi.org/10.1016/j.bone.2015.08.021] [PMID: 26318907]
[69]
Stodieck L. Amgen countermeasures for bone and muscle loss in space and on Earth etrieved on October 9th 2018 https: //www.nasa.gov/sites/default/files/files/issrdc_2013-07-17-0800_stodieck2013.pdf
[70]
Assessment of myostatin inhibition to prevent skeletal muscle atrophy and weakness in mice exposed to long-duration spaceflight (Rodent Research-3-Eli Lilly) - 052417 retrieved on September 30th 2018 https://www.nasa.gov/mission_pages/station/research/experiments/1722.html
[71]
James AW, Shen J, Zhang X, et al. NELL-1 in the treatment of osteoporotic bone loss Nature Comms 2015; 6: 7362.
[72]
Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner 1991; 15(3): 175-91.
[http://dx.doi.org/10.1016/0169-6009(91)90124-I] [PMID: 1773131]
[73]
Systemic therapy of NELL-1 for osteoporosis (Rodent Re-search-5 (RR-5)) - 090518retrieved on October 4th 2018 https: //www.nasa.gov/mission_pages/station/research/experiments/2283.html
[74]
Rodent research-6 (SpaceX-13) retrieved on September 30th 2018 https://www.nasa.gov/ames/research/space-biosciences/rodent-research-6-spacex-13
[75]
Wannenes F, Magni L, Bonini M, et al. In vitro effects of Beta-2 agonists on skeletal muscle differentiation, hypertrophy, and atrophy. World Allergy Organ J 2012; 5(6): 66-72.
[PMID: 23283108]
[76]
Salazar-Degracia A, Busquets S, Argilés JM, Bargalló-Gispert N, López-Soriano FJ, Barreiro E. Effects of the beta2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia. Biochimie 2018; 149: 79-91.
[http://dx.doi.org/10.1016/j.biochi.2018.04.009] [PMID: 29654866]
[77]
Busquets S, Toledo M, Sirisi S, et al. Formoterol and cancer muscle wasting in rats: Effects on muscle force and total physical activity. Exp Ther Med 2011; 2(4): 731-5.
[http://dx.doi.org/10.3892/etm.2011.260] [PMID: 22977567]
[78]
Harcourt LJ, Schertzer JD, Ryall JG, Lynch GS. Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue. Neuromuscul Disord 2007; 17(1): 47-55.
[http://dx.doi.org/10.1016/j.nmd.2006.08.012] [PMID: 17134898]
[79]
Greig CA, Johns N, Gray C, et al. Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy. Support Care Cancer 2014; 22(5): 1269-75.
[http://dx.doi.org/10.1007/s00520-013-2081-3] [PMID: 24389826]
[80]
Toledo M, Springer J, Busquets S, et al. Formoterol in the treatment of experimental cancer cachexia: Effects on heart function. J Cachexia Sarcopenia Muscle 2014; 5(4): 315-20.
[http://dx.doi.org/10.1007/s13539-014-0153-y] [PMID: 25167857]
[81]
von Haehling S, Anker SD. Treatment of cachexia: An overview of recent developments. Int J Cardiol 2015; 184: 736-42.
[http://dx.doi.org/10.1016/j.ijcard.2014.10.026] [PMID: 25804188]
[82]
Study looks at efficacy and metabolism of azonafide-based ADCs in microgravityretrieved on October 4th 2018 from 2018 https://adcreview.com/tag/azonafide-based-adc/
[83]
Costa-Almeida R, Granja PL, Gomes ME. Gravity, tissue engineering and the missing link. Trends Biotechnol 2018; 36(4): 343-7.
[http://dx.doi.org/10.1016/j.tibtech.2017.10.017] [PMID: 29153346]
[84]
Grimm D, Egli M, Krüger M, et al. Tissue engineering under microgravity conditions-use of stem cells and specialized cells. Stem Cells Dev 2018; 27(12): 787-804.
[http://dx.doi.org/10.1089/scd.2017.0242] [PMID: 29596037]
[85]
Aleshcheva G, Bauer J, Hemmersbach R, et al. Scaffold-free tissue formation under real and simulated microgravity conditions. Basic Clin Pharmacol Toxicol 2016; 119(Suppl. 3): 26-33.
[http://dx.doi.org/10.1111/bcpt.12561] [PMID: 26826674]
[86]
Xue L, Li Y, Chen J. Duration of simulated microgravity affects the differentiation of mesenchymal stem cells. Mol Med Rep 2017; 15(5): 3011-8.
[http://dx.doi.org/10.3892/mmr.2017.6357] [PMID: 28339035]
[87]
Yin H, Wang Y, Sun X, et al. Functional tissue-engineered microtissue derived from cartilage extracellular matrix for articular cartilage regeneration. Acta Biomater 2018; 77: 127-41.
[http://dx.doi.org/10.1016/j.actbio.2018.07.031] [PMID: 30030172]
[88]
Wotring VE, Pour S. New pharmacology studies on the ISS retrieved on August 22nd https: //ntrs.nasa.gov/archive/ nasa/casi.ntrs.nasa.gov/20140013149.pdf
[89]
Du B, Daniels VR, Vaksman Z, Boyd JL, Crady C, Putcha L. Evaluation of physical and chemical changes in pharmaceuticals flown on space missions. AAPS J 2011; 13(2): 299-308.
[http://dx.doi.org/10.1208/s12248-011-9270-0] [PMID: 21479701]
[90]
Wotring VE. Chemical potency and degradation products of medications stored over 550 days at the International Space Station. AAPS J 2016; 18(1): 210-6.
[http://dx.doi.org/10.1208/s12248-015-9834-5] [PMID: 26546565]
[91]
Chuong MC, Prasad D, Leduc B, Du B, Putcha L. Stability of vitamin B complex in multivitamin and multimineral supplement tablets after space flight. J Pharm Biomed Anal 2011; 55(5): 1197-200.
[http://dx.doi.org/10.1016/j.jpba.2011.03.030] [PMID: 21515013]
[92]
Shende C, Smith W, Brouillette C, Farquharson S. Drug stability analysis by Raman spectroscopy. Pharmaceutics 2014; 6(4): 651-62.
[http://dx.doi.org/10.3390/pharmaceutics6040651] [PMID: 25533308]
[93]
Mehta P, Bhayani D. Impact of space environment on stability of medicines: Challenges and prospects. J Pharm Biomed Anal 2017; 136: 111-9.
[http://dx.doi.org/10.1016/j.jpba.2016.12.040] [PMID: 28068518]
[94]
Dantuma D, Elmaddawi R, Pathak Y, et al. Impact of simulated micrigravity on nanoemulsion stability – a preliminary research. Am J Med Biol Res 2015; 3: 102-6.
[95]
Popova M, Isayev O, Tropsha A. Deep reinforcement learning for de novo drug design. Sci Adv 2018; 4(7)eaap7885
[http://dx.doi.org/10.1126/sciadv.aap7885] [PMID: 30050984]
[96]
Cortese F, Klokov D, Osipov A, et al. Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization. Oncotarget 2018; 9(18): 14692-722.
[http://dx.doi.org/10.18632/oncotarget.24461] [PMID: 29581875]
[97]
Zahradka K, Slade D, Bailone A, et al. Reassembly of shattered chromosomes in Deinococcus radiodurans. Nature 2006; 443(7111): 569-73.
[http://dx.doi.org/10.1038/nature05160] [PMID: 17006450]
[98]
Battista JR, Earl AM, Park M-J. Why is Deinococcus radiodurans so resistant to ionizing radiation? Trends Microbiol 1999; 7(9): 362-5.
[http://dx.doi.org/10.1016/S0966-842X(99)01566-8] [PMID: 10470044]
[99]
Chakraborty N, Gautam A, Muhie S, Miller SA, Jett M, Hammamieh R. An integrated omics analysis: Impact of microgravity on host response to lipopolysaccharide in vitro. BMC Genomics 2014; 15: 659.
[http://dx.doi.org/10.1186/1471-2164-15-659] [PMID: 25102863]
[100]
McCarville JL, Clarke ST, Shastri P, et al. Spaceflight influences both mucosal and peripheral cytokine production in PTN-Tg and wild type mice. PLoS One 2013; 8(7) e68961
[http://dx.doi.org/10.1371/journal.pone.0068961] [PMID: 23874826]
[101]
Crucian BE, Choukèr A, Simpson RJ, et al. Immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions. Front Immunol 2018; 9: 1437.
[http://dx.doi.org/10.3389/fimmu.2018.01437] [PMID: 30018614]
[102]
Barrila J, Ott CM, LeBlanc C, et al. Spaceflight modulates gene expression in the whole blood of astronauts. NPJ Microgravity 2016; 2: 16039.
[http://dx.doi.org/10.1038/npjmgrav.2016.39] [PMID: 28725744]
[103]
Chaussabel D. Assessment of immune status using blood transcriptomics and potential implications for global health. Semin Immunol 2015; 27(1): 58-66.
[http://dx.doi.org/10.1016/j.smim.2015.03.002] [PMID: 25823891]
[104]
Zea L, Larsen M, Estante F, et al. Phenotypic changes exhibited by E. coli cultured in space. Front Microbiol 2017; 8: 1598.
[http://dx.doi.org/10.3389/fmicb.2017.01598] [PMID: 28894439]
[105]
Aunins TR, Erickson KE, Prasad N, et al. Spaceflight modifies Escherichia coligene expression in response to antibiotic exposure and reveals role of oxidative stress response. Front Microbiol 2018; 9: 310.
[http://dx.doi.org/10.3389/fmicb.2018.00310] [PMID: 29615983]
[106]
Taylor PW. Impact of space flight on bacterial virulence and antibiotic susceptibility. Infect Drug Resist 2015; 8: 249-62.
[http://dx.doi.org/10.2147/IDR.S67275] [PMID: 26251622]
[107]
Klaus DM, Howard HN. Antibiotic efficacy and microbial virulence during space flight. Trends Biotechnol 2006; 24(3): 131-6.
[http://dx.doi.org/10.1016/j.tibtech.2006.01.008] [PMID: 16460819]
[108]
Higginson EE, Galen JE, Levine MM, et al. Microgravity as a biological tool to examine host-pathogen interactions and to guide development of therapeutics and preventatives that target pathogenic bacteria. Pathog Dis 2016; 74 ftw095
[http://dx.doi.org/10.1093/femspd/ftw095]
[109]
Nair A. A change in microbial virulence under simulated microgravity might hold a strategic value for Salmonella. I Infect Non Infect Dis 2015; 1: 009.
[110]
Mermel LA. Infection prevention and control during prolonged human space travel. Clin Infect Dis 2013; 56(1): 123-30.
[http://dx.doi.org/10.1093/cid/cis861] [PMID: 23051761]
[111]
Rosenzweig JA, Abogunde O, Thomas K, et al. Spaceflight and modeled microgravity effects on microbial growth and virulence. Appl Microbiol Biotechnol 2010; 85(4): 885-91.
[http://dx.doi.org/10.1007/s00253-009-2237-8] [PMID: 19847423]
[112]
Nickerson CA, Ott CM, Mister SJ, Morrow BJ, Burns-Keliher L, Pierson DL. Microgravity as a novel environmental signal affecting Salmonella enterica serovar Typhimurium virulence. Infect Immun 2000; 68(6): 3147-52.
[http://dx.doi.org/10.1128/IAI.68.6.3147-3152.2000] [PMID: 10816456 ]
[113]
Wilson JW, Ott CM, zuBentrup KH. Space flight alters bacterial gene expression and virulence and reveals a role for global regulator HfqProc Natl AcadSci USA 2007. 104: 16299-304.
[114]
Li J, Guo Y, Xu G, et al. Effects of microgravity on the phenotype, genome and transcriptome of Streptococcus pneumonia. Res Rev J Microbiol Biotechnol 2016; 5: 107-14.
[115]
National Laboratory Pathfinder - Vaccine - Methicillin-resistant. Staphylococcus aureus (NLP-Vaccine-MRSA) - 032818retrieved on October 4th www.nasa.gov/mission_pages/station/research/experiments/789.html
[116]
Huangfu J, Zhang G, Li J, Li C. Advances in engineered microorganisms for improving metabolic conversion via microgravity effects. Bioengineered 2015; 6(4): 251-5.
[http://dx.doi.org/10.1080/21655979.2015.1056942] [PMID: 26038088]
[117]
Benoit MR, Li W, Stodieck LS, et al. Microbial antibiotic production aboard the International Space Station. Appl Microbiol Biotechnol 2006; 70(4): 403-11.
[http://dx.doi.org/10.1007/s00253-005-0098-3] [PMID: 16091928]
[118]
Fang A, Pierson DL, Mishra SK, Koenig DW, Demain AL. Secondary metabolism in simulated microgravity: β-lactam production by Streptomyces clavuligerus. J Ind Microbiol Biotechnol 1997; 18(1): 22-5.
[http://dx.doi.org/10.1038/sj.jim.2900345] [PMID: 9079284]
[119]
Fang A, Pierson DL, Mishra SK, Demain AL. Relief from glucose interference in microcin B17 biosynthesis by growth in a rotating-wall bioreactor. Lett Appl Microbiol 2000; 31(1): 39-41.
[http://dx.doi.org/10.1111/j.1472-765X.2000.00762.x] [PMID: 10886612]
[120]
Fang A, Pierson DL, Mishra SK, Demain AL. Growth of Steptomyces hygroscopicus in rotating-wall bioreactor under simulated microgravity inhibits rapamycin production. Appl Microbiol Biotechnol 2000; 54(1): 33-6.
[http://dx.doi.org/10.1007/s002539900303] [PMID: 10952002]
[121]
Luo A, Gao C, Song Y, Tan H, Liu Z. Biological responses of a Streptomyces strain producing-Nikkomycin to space flight Space Med Med Eng (Beijing) 1998; 11(6): 411-4.
[PMID: 11543377]
[122]
Zhou J, Sun C, Wang N, et al. Preliminary report on the biological effects of space flight on the producing strain of a new immunosuppressant, Kanglemycin C. J Ind Microbiol Biotechnol 2006; 33(8): 707-12.
[http://dx.doi.org/10.1007/s10295-006-0118-z] [PMID: 16609855]
[123]
Influence of microgravity on the production of Aspergillus secondary metabolites (IMPAS) – a novel drug discovery ap-proach with potential benefits to astronauts’ health (Micro-10) - 101117 retrieved on October 4th 2018 from https: //www. nasa.gov/mission_pages/station/research/experiments/1299.html
[124]
Orlov O, Belakovsky M, Kussmaul A. Potential markets for application of space medicine achievements. Acta Astronaut 2014; 104: 412-8.
[http://dx.doi.org/10.1016/j.actaastro.2014.05.006]
[125]
Ruyters G, Stang K. Space medicine 2025 – a vision. Space Medicine driving terrestrial medicine for the benefit of people on Earth. REACH – Rev. Hum Space Explor 2016; 1: 55-62.
[126]
Morokuma J, Durant F, Williams KB, et al. Planarian regeneration in space: Persistent anatomical, behavioral, and bacteriological changes induced by space travel. Regeneration (Oxf) 2017; 4(2): 85-102.
[http://dx.doi.org/10.1002/reg2.79] [PMID: 28616247]