Parasitic Connection between COVID-19 and Diarylamidines: History
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Contributor:
John Hulme

As emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants (Omicron) continue to outpace and negate combinatorial vaccines and monoclonal antibody therapies targeting the spike protein (S) receptor binding domain (RBD), the appetite for developing similar COVID-19 treatments has significantly diminished, with the attention of the scientific community switching to long COVID treatments.

  • long COVID
  • serine protease
  • diarylamidines

1. Introduction

As of 8 March 2023 (accessed: https://coronavirus.jhu.edu/map.html), more than 676 million COVID-19 cases and 6.8 million deaths had been reported globally. During that time, SARS-CoV-2 underwent significant mutations [1], resulting in Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Gamma (P.1), and Omicron variants of concern (VOC). The most recent of these is the Omicron subvariant XBB.1.5, which is expected to be the aetiology of the majority of USA COVID-19 infections by early 2023 [2][3][4][5]. Unlike the original Wuhan strain, Omicron variants induce clinical symptoms associated with the upper respiratory tract and larynx, where the airway temperature is significantly lower [6], the viral replication rate is considerably higher [7], and the hosts’ immune response is reduced. Such conditions contribute to Omicron’s high transmissibility and ability to evade the hosts’ immune response.
The high transmissibility of Omicron has not only proved its infection and reinfection potential in humans and semi-domesticated species [8][9], but recent reports suggest the variant is prevalent in wild species [10]. Moreover, studies suggest that the requirement for P3 arginine in S1/S2 for furin cleavage common to different hosts provides a window for zoonotic transfer [11]. Accordingly, the World Health Organization has stressed the importance of veterinary and wastewater surveillance of de novo mutations and antigenic shifts in other species that could later appear in humans [12]. Water surveillance in cities and provinces has provided some unique insights into the emergence of the Wuhan and new Omicron strains and the transition from inter-pandemic to pandemic periods. In addition, previous studies have shown that increasing wastewater temperatures from 4 °C to 10 °C can more than double the decay rate of free-form SARS-CoV-2 RNA, measured by detecting the N1 and N2 genes [12]. However, water surveillance relates to viral identification and not the exact origins of the Wuhan and Omicron strains, the latter first being identified in South Africa on 24 November 2021 [13][14].

2. Bats, Pangolins, Parasites, and Diarylamidines: Making the Connection

An attempt to address the critical issue of the intermediate hosts of SARS-CoV-2 was recently presented by Tang et al. [15] in the general context of human coronaviruses but was left unresolved with additional vectors missing. Currently, the vectors associated with potential intermediate hosts (bats and pangolins) [16] include bat flies (Diptera: Nycteribiidae and Streblidae), bugs (Hemiptera: Cimicidae and Polyctenidae) that transmit blood ectoparasites (protozoans Trypanosoma spp. and Plasmodium spp.) [17][18], Wolkberg and Kaeng Khoi RNA viruses (Bunyavirales: Bunyaviridae and Peribunyaviridae), and dengue virus (Flaviviridae) [19]. A plethora of divergent viruses and different vectors found on live bats collected from Yunnan Province, China, between 2012 and 2015 was recently examined by Xu et al. [20]. Researchers encountered mainly arthropod-specific viruses and three possible arboviruses, suggesting that viral spillage between bats and common parasitic arthropods rarely occurs; whether this is the case for other parasite arthropods such as Hemiptera (triatomine bugs) could not be addressed. Hemiptera is renowned for its ability to transmit Trypanosoma spp., which are found in approximately 100 bat species worldwide [21]. The potential vectors for T. cruzi involve > 130 species of triatomine insects, five of which are epidemiologically more significant: Triatoma infestans, Triatoma brasiliensis, Triatoma dimidiata, Rhodnius prolixus, and Panstrongylus megistus. Currently, there are no documented cases of Hemiptera transmitting Trypanosoma species from bats to humans. However, just before the start of the pandemic, a related Trypanosoma cruzi genotype, specifically T. cruzi (TcBat), was reported for the first time in the brains of several bat species sourced from Yunnan Province (Noctilio spp., Myotis spp., and Artibeus spp.) [22]; unfortunately, the researchers did not test the blood or visit the animals to test for arthropods during the time of capture (2010–2015). TcBat was initially discovered in South America and has been detected in a Colombian child [23] and human mummies. Several bat families house the genotype, and phylogenic studies suggest that TcBat is a monophyletic lineage predominant in Colombia, Brazil, and Panama. In addition to TcBat, another bat trypanosome species reported to infect mammals and a handful of humans in Central America and north-western South America is Trypanosoma rangeli (T. rangeli) [24].
Before 2000, the origins of bat trypanosomes remained elusive until extensive evolutionary and taxonomic studies relating to the genus Trypanosoma resulted in the “bat-seeding hypothesis” proposed by Hamilton et al. in 2012. The hypothesis suggested that T. cruzi was the first bat trypanosome due to its expansive host range and employment of alternative vectors (triatomine bugs) permitting its transmission among New and Old-World terrestrial mammals. Additional multilocus phylogenetic analyses on multiple bat trypanosomal species sourced from Europe, South America, Africa, China, and Japan confirmed their placement within the T. cruzi clade, validating the hypothesis [24]. Hamilton further postulated that said clade probably arose from an ancestral group of isolated trypanosomes exclusively evolving in bats with multiple spill-over events into terrestrial mammals. The T. cruzi population is classified into six discrete typing units (DTUs): TcI to TcVI, with the recently named TcBat as the seventh. Trypanosomes within the T. cruzi clade are distributed into three main phylogenetic lineages.
Trypanosoma spp. are extracellular and intravascular blood parasites that cause debilitating acute or chronic disease in camels, cattle, humans, and other domestic animals. There are two phases of infection, acute and chronic, with the former associated with bone marrow hypoplasia anaemia, thrombocytopenia, and leukopenia in mammalian hosts [21]. Cardiomyopathy is the most common clinical outcome, and, until 2019, Trypanosoma infections and the associated disease (Trypanosomiasis) were endemic in 36 sub-Saharan African countries [25]. Strategies employed by trypanosomes to evade the host immune system include antigenic variation, induction of suppressor macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells [26].
Another parasitic disease [26] endemic on many continents [27] is babesiosis, a tickborne infection transmitted to humans by the bite of Ixodes scapularis, harbouring the parasite Babesia microti (B. microti) [28]. Prevalent in vertebrates, B. microti was recently found in 53 confiscated rare Sunda pangolins native to Thailand [26]. Moreover, additional reports found evidence of SARS-CoV-2-related coronaviruses circulating in Sunda pangolins [27]. Currently, there are no studies investigating B. microti and SARS-CoV-2 co-infections in humans or pangolins and the transfer of immunosuppressive factors, primarily due to the lack of testing and suitably available animal models. Furthermore, other reports show that co-infections involving Babesia. spp. [29] and Trypanosoma. spp. [30] are common with other parasitic species. In addition to blood parasites, several bacteria, including Borrelia burgdorferi sensu lato (B. burgdorferi), benefit from co-infection with Babesia, which can prolong severe Lyme arthritis in mice when compared to controls [30][31].
However, exceptions do occur; for example, Plasmodium spp. infection prior to SARS-CoV-2 infection was reported to contribute to the disease’s poor prognosis and was seen to reduce the incidence of malaria in endemic regions [32][33][34]. Furthermore, additional investigations suggested that high exposure to malaria compared to low exposure prior to SARS-CoV-2 infection offered better protection against severe or critical COVID-19 [35].
Diarylamidines, diminazene aceturate (DIZE), and pentamidine have been used to treat Trypanosomiasis (T. cruzi and T. brucei—Chagas disease and African Sleeping. sickness), Leishmania, and Babesiosis in humans and cattle for decades [36][37][38][39]. DIZE and pentamidine are transported into trypanosomes, exerting their protozoalcidal abilities by targeting the adenine–thymine (A-T)-rich hairpin loops in circular and kinetoplast DNA resulting in the complete and irreparable nucleic acid loss. In addition, diarylamidines can also bind to mitochondrial II topoisomerase and transfer RNA [40]. Outside of their interactions with parasites, numerous studies have demonstrated that DIZE and pentamidine can act as bacterial growth inhibitors and adjuvants to common antibiotics [41][42][43][44][45][46][47][48]. Moreover, DIZE was shown to inhibit the production of lipopolysaccharide (LPS) endotoxins [49][50], whilst pentamidine interacts with LPS via lipid A [51][52] (Table 1).
Table 1. Antiparasitic and synergistic capabilities of diminazene aceturate and pentamidine when used separately or in conjunction with antibiotics.

Diarylamidines & Combinations

Pathogen/Disease

Hosts/Experimental

Findings

References

DIZE & AZI

T. brucei

Albino Rats

↓ Parasitaemia

↓ Leukocytosis

[44]

DIZE

T. congolense

BALB/c mice

C57BL/6 mice

↓ LPS-induced production

↓ IL-6, IL-12, TNF and IFN-γ

[41]

DIZE

S. mansoniex vivo

mice

↓ Aminotransferase levels

↓ Immature and adult parasites

[53]

DIZE

T. congolense

Pre-treated macrophages

↓ Phosphorylation of mitogen-activated protein kinase (p38), STAT1 and STAT3

[49]

CLD, DIZE, ACE, IMD

C. babesiosis

Dogs

↓ Malaise, fatigue, chills, fever

[39]

DIZE, CHL, STP

Antibiotic-resistant

K. pneumoniae, S. aureus and E. coli

Minimal inhibitory concentrations (MICs) assay

↑ Gram-negative and positive bacterial sensitivity to antibiotics

↓ in MIC

[43]

PENT, colistin

T. brucei rhodesiense

66-year-old female

↓ Parasitaemia by 75% (trypomastigotes)

[38]

PENT

A. baumannii

Murine Infection Model

↑ sensitivity of colistin-resistant A. baumannii to gram-positive antibiotics

[46]

PENT analogue (P35)

A. baumannii & K. pneumoniae.

Murine model

↑ sensitivity of colistin-resistant A. baumannii to gram-positive antibiotics

[47]
Diminazene aceturate (DIZE), Pentamidine (PENT), Chloramphenicol (CHL), Streptomycin (STP), Imidocarb dipropionate (IMD), Clindamycin (CLD), Azithromycin (AZI), Aceturate (ACE). Trypanosoma brucei (T. brucei), Trypanosoma congolense (T. congolense), Klebsiella pneumoniae (K. pneumoniae), Schistosoma mansoniex vivo (S. mansoniex vivo), Canine babesiosis (C. babesiosis), Acinetobacter baumannii (A. baumannii), Staphylococcus aureus (S. aureus), Escherichia coli (E. coli).
The modulation of LPS activity via arylamidines and the potential implications regarding potential treatments of numerous diseases associated with aberrant immune activation and coagulation have led to a flurry of animal model studies, including (i) amelioration of neurological pathologies (Alzheimer’s) [54]; (ii) cardiac (atherosclerotic plaque stabilization, cardiac fibrosis) [55][56][57]; (iii) pulmonary (hypertension) [58]; (iv) liver (injury and biliary fibrosis) [59]; (v) diabetic (type 1) [60]; (vi) acute radiation exposure/damaged tissue (ARE) [61] (Table 2).
Table 2. Amelioration of cardiac, neurological, kidney, and systemic experimental models by diminazene aceturate (DIZE).

Diarylamidine

Disease/Pathology

Hosts/Experimental

Findings

References

DIZE

AD

SAMP8 mice

↓ Neuropathology

[54]

DIZE

Liver injury & BF

MDR gene-2 knockout mice

↓ NOX enzyme assembly and ROS generation

↑ myofibroblasts & tissue repair

[59]

DIZE

ATP & HPS

ApoE-Knockout mice

Modulating macrophage response & taurine biosynthesis

[57]

DIZE

CF & DAD

W rats

↑ Protective effect on the heart

under the pathological condition of kidney injury

[55]

DIZE

PHY

SD male rats

↑ Vasoprotective axis of the LRAS, ↑ pulmonary vasoreactivity,

↑ enhanced cardiac function, ↓ inflammatory cytokines

[56]

DIZE

NPP

W diabetic male rats

↑ Glomerular ACE2 & AT2 receptor expression

↓ fibrosis and apoptosis

[60]

DIZE

MORI

WAG/RijCmcr rats

↑ Survivability in rat models of H-ARS and DEARE

[61]

DIZE

CAR

W rats

↑ Acute antiarrhythmic-mic potential in vivo modulation of cardiomyocytes contraction and excitability properties

[62]

Alzheimer’s disease (AD), Senescence Accelerated Mouse (SAMP8), Biliary fibrosis (BF), Multiple Drug Resistant (MDR), Atherosclerotic Plaques (ATP), Hepatic Steatosis (HPS), Cardiac Fibrosis (CF), Diastolic Dysfunction (DAD), Pulmonary Hypertension (PHY), Nephropathy (NPP), Multiorgan Radiation Injury (MORI), Ischemia (IC), Myocardial Infarction (MI), Wistar Rats (W rats), Sprague-Dawley Rats (SD rats), Cardiac Arrhythmia (CAR), Hematologic Acute Radiation Syndrome (H-ARS), Multiorgan Delayed Effects of Acute Radiation Exposure (DEARE), Lung Renin-Angiotensin System (LRAS).

3. Diarylamidines, Serine Proteases

The triazene bridge and the two amidine groups present in the molecular structure of DIZE and, to some extent, pentamidine (amidine groups) are thought to be responsible for their interactions with single-stranded, double-stranded, and supercoiled DNA. [63]. These trypsin/mesotrypsin [64] substrate mimics are charged at neutral pH (poor oral bioavailability) and are part of a group of diarylamidines (diminazene, pentamidine, hydroxysitlbamidine, and 4’,6-diamidino-2-phenylindole, (DAPI)) which inhibit the activity of all ASIC subtypes, including ASIC1a [65], whose blockade has been shown to be beneficial in animal models of Huntington’s and Parkinson’s diseases [66][67], ischemic stroke [68], and multiple sclerosis [69][70].
Due to its nanomolar potency for subtype ASIC1 and its inability (apart from stroke) to cross the blood–brain barrier (free form), DIZE is often limited to usage as a standard drug for in vitro modelling of new ASIC inhibitors [71]. Like many ASIC drugs (hydroxysitlbamidine and pentamidine) [72], diminazene, as well as its metabolite para-amino benzamidine (pABA), are serine protease inhibitors [73]. More recently, a cell-based proteolytic assay investigating the repurposing potential of DIZE and the clinically approved ASIC drugs camostat, nafamostat, and gabexate [74][75][76] for the treatment of mild COVID-19 further demonstrated DIZE’s broad spectrum ability to inhibit the catalytic triad of TMPRSS2 (HIS296, ASP345, and SER44), as well as furin’s active sites (ASN192, LEU227, SER253, ASP258, ASP306, THR367, and SER36). In an attempt to further understand DIZE’s ability to inhibit both proteases, additional modelling studies conducted by the authors revealed that the drug adopted a similar binding pose to that of the furin inhibitor [m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(4-amidomethyl)-benzamidine] MI-52. Additionally, the drug interacted favorably with residues at catalytic and binding sites of TMPRSS2 as well. Collectively, the results suggest that further studies utilizing DIZE in conjunction with other protease inhibitors regarding viral entry in animals and humans may be warranted.
However, DIZE’s ability to reversibly inhibit other proteases does not stop with SARS-CoV-2, specifically regarding the catalytic triad domain (HIS, ASP, and SER) of the trypsin-like peptidase Oligopeptidase B (OPB) [77]. OPB is part of a family of serine prolyl oligopeptidases that contribute to the virulence of Leishmania, Leishmania major, L. amazonensis, trypanosomes, T. cruzi, T. brucei, T. evansi [78][79], and other parasitic diseases, whose OPB catalytic activity favours the carboxyl side of pairing basic amino acid residues. The arginine at the P1 position renders it more vulnerable to trypsin substrate mimics such as DIZE and, to a lesser extent, pentamidine [80]. OpdB has been shown to inactivate atrial natriuretic factor (ANF) in the bloodstream of T. evansi-infected rats [81] by cleaving the hormone at four sites and is resistant to host plasma peptidase inhibitors [82] such as α2-macroglobulin, cystatins, kininogen, antiplasmin, and antithrombin III. Furthermore, OpdB can hydrolyse adrenocorticotropic hormone (ACTH), glucagon, neurotensin, angiotensin I, and vasoactive intestinal polypeptide, resulting in patient hormonal imbalance.
In addition to OpdB, T. brucei also utilizes other prolyl oligopeptidases (POPs). One of them is POP Tc-80, an enzyme involved in degrading large protein substrates such as collagens, fibronectin, and small peptides [83], accelerating the parasitic entry of macrophages and red blood cells (RBCs). Akin to OpdB, POP Tc-80 houses a catalytic triad, providing an additional target for DIZE and pentamidine. Moreover, the blood fluke Schistosoma mansoni responsible for S. mansoni infection (Schistosomiasis) also employs a prolyl oligopeptidase (catalytic triad Ser556, Asp643, and His682), aptly named S. mansoni (SmPOP) to infect muscle tissue, gastrodermis, and the gut lumen in animals and humans [53]. Unsurprisingly, when DIZE was intraperitoneally (IP) administered as a treatment for blood fluke-infected mice, it reduced the worm burden by 87% compared with praziquantel’s 92%, as well as serum alanine and aspartate aminotransferase (ALT) levels (liver markers) [84]. SmPOP is interesting not only because it plays an important role in the second most prevalent parasitic disease (Schistosomiasis) in sub-Saharan Africa and parts of Brazil [85], but because of its ability to cleave multiple RAS human peptides (Ang I and Bradykinin), which potentially allows it to modulate the RAS system. The ability of schistosomes to further influence the host is also reflected in work by Wang et al. [86], which demonstrated that the parasite could cleave the host co-factor kininogen, a regulatory enzyme involved in multiple stages of the coagulation and inflammatory processes within the host.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24076583

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