Review biomolecules Acetylcholinesterase: The “Hub” for NeurodegenerativeReview Diseases and Chemical Weapons Acetylcholinesterase: The “Hub” for Convention Neurodegenerative Diseases and Chemical WeaponsSamir F. de A. Cavalcante Convention 1,2,3,*, Alessandro B. C. Simas 2,*, Marcos C. Barcellos 1, Victor G. M. de Oliveira 1, Roberto B. Sousa 1, Paulo A. de M. Cabral 1 and Kamil Kuča 3,*and Tanos C. C. França 3,4,* Samir F. de A. Cavalcante 1,2,3,* , Alessandro B. C. Simas 2,*, Marcos C. Barcellos 1, Victor1 Institute G. M. ofde Chemical, Oliveira Biological,1, Roberto Radiological B. Sousa and1, Paulo Nuclear A. Defense de M. Cabral (IDQBRN),1, Kamil Brazilian Kuˇca Army3,* and TanosTechnological C. C. França Center3,4,* (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; [email protected] (M.C.B.); [email protected] (V.G.M.d.O.); [email protected] 1 Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN), Brazilian Army (R.B.S.); [email protected] (P.A.d.M.C.) Technological Center (CTEx), Avenida das Américas 28705, Rio de Janeiro 23020-470, Brazil; 2 [email protected] Mors Institute of Research (M.C.B.); on Natural [email protected] Products (IPPN), Federal (V.G.M.d.O.); University of Rio de Janeiro (UFRJ), CCS,[email protected] Bloco H, Rio de Janeiro (R.B.S.); 21941-902, [email protected] Brazil (P.A.d.M.C.) 32 DepartmentWalter Mors of Institute Chemistry, of Research Faculty of on Science, Natural Un Productsiversity (IPPN), of Hradec Federal Králové, University Rokitanskeho of Rio de 62, Janeiro 50003 (UFRJ), HradecCCS, Bloco Králové, H, Rio Czech de JaneiroRepublic 21941-902, Brazil 43 LaboratoryDepartment of ofMolecular Chemistry, Modelling Faculty ofApplied Science, to UniversityChemical and of Hradec Biological Krá lovDefenseé, Rokitanskeho (LMACBD), 62, Military Institute50003 Hradec of Engineering Králové, (IME), Czech Praça Republic General Tibúrcio 80, Rio de Janeiro 22290-270, Brazil *4 Correspondence:Laboratory of Molecular [email protected] Modelling Applied (S to.F.d.A.C.); Chemical [email protected] and Biological Defense (A.B.C.S.); (LMACBD), [email protected] Institute of(K.K.); Engineering [email protected] (IME), Praça General (T.C.C.F.); Tibúrcio Tel. 80, +55-21-998-419-561 Rio de Janeiro 22290-270, (S.F.d.A.C.); Brazil +55-21- * 998-744-886Correspondence: (A.B.C.S.); [email protected] +420-603-289-166 (K.K.) (S.F.d.A.C.); [email protected] (A.B.C.S.); [email protected] (K.K.); [email protected] (T.C.C.F.); Tel.: +55-21-998-419-561 (S.F.d.A.C.); Received:+55-21-998-744-886 16 February 2020; (A.B.C.S.); Accepted:+420-603-289-166 3 March 2020; (K.K.) Published: 7 March 2020 Abstract:Received: 16This February article 2020; Accepted:describes 3 Marchacetylcholinesterase 2020; Published: 7 March(AChE), 2020 an enzyme involved in parasympathetic neurotransmission, its activity, and how its inhibition can be pharmacologically Abstract:useful for Thistreating article dementia, describes caused acetylcholinesterase by Alzheimer’s (AChE), disease, an enzymeor as a involvedwarfare method in parasympathetic due to the actionneurotransmission, of nerve agents. its activity, The chemical and how concepts its inhibition related can to bethe pharmacologically irreversible inhibition useful of for AChE, treating its reactivation,dementia, caused and byaging Alzheimer’s are discussed, disease, along or as awith warfare a relationship method due to to the actioncurrent of international nerve agents. legislationThe chemical on conceptschemical relatedweapons. to the irreversible inhibition of AChE, its reactivation, and aging are discussed, along with a relationship to the current international legislation on chemical weapons. Keywords: acetylcholinesterase; Alzheimer’s disease; nerve agents; Chemical Weapons Convention Keywords: acetylcholinesterase; Alzheimer’s disease; nerve agents; Chemical Weapons Convention 1. Introduction 1. Introduction The use of chemical weapons (CW) is quite common throughout history. Over time, the use of incendiaries,The use darts, of chemical spears, weapons and arrows (CW) impregnated is quite common with poisons throughout from history.different Over organisms, time, the animals, use of andincendiaries, plants, the darts, lethality spears, of andsubstances arrows impregnatedused for warfare with have poisons been from dramatically different organisms,improved. animals,Despite internationaland plants, the agreements lethality of already substances in existence used for by warfare the end have of 19th been century, dramatically these improved.did not inhibit Despite the large-scaleinternational use agreements of CW during already World in existence War I (WWI) by the (1914–1918), end of 19th when century, millions these didof casualties not inhibit were the provokedlarge-scale mainly use of by CW phosgene, during World chlorine, War and, I (WWI) particularly, (1914–1918), sulfur when mustard millions (HD of1) (Figure casualties 1). wereThis compound,provoked mainly due to byits phosgene,physicochemical chlorine, characteristic and, particularly,s, is known sulfur as “area mustard denial (HD weapon”,1) (Figure precluding1). This furthercompound, access due to tothe its place physicochemical where it has characteristics,been deployed is[1]. known as “area denial weapon”, precluding further access to the place where it has been deployed [1]. S Cl Cl 1 Biomolecules 2020, 10, x; doi: Figure 1. Sulfur mustard HD1. www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, 414; doi:10.3390/biom10030414 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x 2 of 21 Biomolecules 2020, 10, 414 2 of 22 Figure 1. Sulfur mustard HD1. After WWI and more actively during WWII, while looking for new pesticides, pesticides, German scientists developed a a series series of of pentavalent pentavalent phosphorus phosphorus compounds compounds that that contained contained a leaving a leaving group group such suchas a halogen.as a halogen. They Theydiscovered discovered that thatthese these compounds compounds were were very very toxic, toxic, and and capable capable of of inhibiting acetylcholinesterase (AChE). (AChE). These These findings findings resulted resulted in in the the weaponization weaponization of of the the first first nerve nerve agents, agents, 2 3 4 called also G-agents, which included sarin 2 (GB), soman 3 (GD), and tabun 4 (GA) (Figure2 2).). SuchSuch CW were produced and stockpiled, but never used during WWIIWWII. [ 1[1–11]–11]. Figure 2. G-Agents. Figure 2. G-Agents. Later, during the 1950s, aiming to produce more effective effective pesticides, groups in the former Soviet Union, Great Britain, Sweden, and the United United St Statesates developed developed other other organophosphorus organophosphorus compounds which were more toxic and persistentpersistent (less volatile)volatile) than G-agents. These new chemicals were then named V-agents, whichwhich areare phosphonothioatesphosphonothioates ( 5(5and and6 ,6 Figure, Figure3)[ 3)4 [4,12–15].,12–15]. Like Like sulfur sulfur mustard mustard HD HD1, 1these, these compounds compounds can can be be similarly similarly regarded regarded as as “area “area denial denial weapons” weapons” [2, 8[2,8].]. Figure 3. V-Agents.V-Agents. Although they were not used used in in the the World World Wars Wars,, the international community could soon testify testify their potential potential as Weapons Weapons of Mass Destruction (W (WMD)MD) when, in the 1980s, Saddam Hussein’s troops used chemical artillery containing G-agents, GB 2 and GA 4, along along with with sulfur sulfur mustard mustard HD 1, against civilian and military targets during the Iran–Iraq war. The tragic events in the Kurdish Kurdish city of Halabja Halabja show how abhorrent can be the use of these substanc substanceses as warfare agents [16–18]. [16–18]. In In 1994 1994 and and 1995, 1995, Japan waswas strickenstricken byby two two episodes episodes when when GB GB2 2was was employed employed in in the the terrorist terrorist actions actions carried carried out out by theby thesect sectAum Aum Shinrikyo Shinrikyo, provoking, provoking casualties casualties among among civilians civilians and and first first responders responders [4,19 [4,19–22].–22]. Although manymany papers papers have have dealt deal witht with chemical chemical warfare warfare over theover years, the theyears, use the of CW use is of currently CW is currentlya pressing a subject.pressing Recently,subject. Rece chemicalntly, chemical warfare agentswarfare have agents made have headlines made headlines due to theirdue to alleged their allegeddeployment deployment in the Civil in the War Civil ongoing War ongoing in Syria in (2011–) Syria and(2011–) as meansand as ofmeans murdering of murdering the North the Korean North Koreannational national Kim Jun Kim Nam Jun at theNam Kuala at the Lumpur Kuala InternationalLumpur International Airport in Airport 2017. A in report 2017. from A report Malaysian from Malaysianauthorities authorities confirmed thatconfirmed VX was that used VX by was the used perpetrators by the perpetrators [4,23–42]. [4,23–42]. In 2018, events events that that occurred occurred in in Salisbury Salisbury and and Amesbury, Amesbury, Great Britain, where a former Russian agent and other people were poisoned with an “unknown, high-purity grade military agent” with possible neurotoxic eeffects,ffects, prompted discussions about the so-called “Novichok” agents.