Table 1.

CTPsyn as a drug target for diseases caused by viruses, bacteria, and parasites

Disease	Role of CTPsyn	Reference
Toxoplasmosis (caused by Toxoplasma gondii)	TgCTPS is essential for the parasite T. gondii survival, and it forms stage-dependent foci like structure, where extracellular parasite forms more pronounced foci than the intracellular parasite as the former requires low CTPS activity; thus, filaments were used to store the enzyme. Meanwhile, upon infection into host cell, the parasite requires high CTPS activity, thus releasing the stored enzymes from the filaments. T. gondii have restricted capacity to salvage CTP synthesis; hence, its dependency on de novo CTP biosynthesis with the aid of CTPsyn could be used as a potential anti-parasitic target	(Narvaez-Ortiz et al. 2018)
African sleeping sickness (caused by Trypanosoma brucei)	T. brucei has a low level of CTP due to its limitation in the de novo CTP synthesis and lacking ability to salvage CTP. The parasite CTP level was severely reduced with DON and acivicin, inhibiting the proliferation of the parasite in the host. Therefore, a CTPsyn inhibitor could be a potential drug target for treatment of sleeping sickness	(Hofer et al. 2001; Fijolek et al. 2007)
Tuberculosis (caused by Mycobacterium tuberculosis)	Drug-resistant M. tuberculosis is identified to be resistant to two different compounds. Both compounds were activated by EthA monooxygenase, and its metabolite was found to target CTPyn, PyrG. Therefore, this validates that targeting CTPsyn PyrG could be a potential drug target to treat tuberculosis (Mori et al. 2015). 4-(Pyridin-2-yl) thiazole derivatives were found to target PyrG activity, but low activity towards human CTPsyn, hence making it an attractive target to combat tuberculosis	(Esposito et al. 2017)
Covid-19 (caused by SARS-CoV-2)	CTPS1 is hijacked by SARS-CoV-2 to mute IFN induction to shut down downstream immune responses and to promote virus replication in the host cell. CTPS1 inhibitor molecules could restore the IFN induction and shortage of CTP impedes virus replication in infected cells. This makes CTPS1 as a potential antiviral therapy target that could resist SARS-CoV-2 variants via restoring innate immune response upon infection (Fig. 8)	(Rao et al. 2021)
Infectious mononucleosis and cancers (caused by Epstein-Barr virus (EBV))	Patients with CTPS1 deficiency often have high EBV viral loads due to impaired T-cell surveillance. CTPS1/2 could be a potential therapeutic target for lymphoproliferative diseases caused by EBV	(Hislop et al. 2007; Liang et al. 2021)
Pox virus infections	Carbodine [cyclopentyl cytosine (C-Cyd)] and cyclopentenyl cytosine (Ce-Cyd) are antiviral agents that inhibit CTPsyn activity. These inhibitors suppress RNA synthesis and induce cytotoxicity in proliferating cells	(Marquez et al. 1988)
Antibiotic resistance (by Bacillus subtilis)	To develop anti-infectives, PyrG, CTPsyn is targeted by isoquinoline compounds, which have a higher antibiotic effect on B. subtilis mutant lacking all four class A penicillin-binding proteins (PBPs). Since the effect of polymerization of CTPsyn in human and bacteria are completely opposite, it could be a therapeutic target to achieve desired inhibition specificity	(Emami et al. 2020)
Respiratory tract infection (RTI) (caused by Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae)	2-(3-[3-oxo-1,2-Benzisothiazol-2(3H)-yl]phenylsulfonylamino) benzoic acid (compound G1) could be the potential anti-microbial agent that targets PyrG, CTPsyn. Compound G1 could compete with ATP and/or UTP to bind with PyrG in order to inhibit CTPsyn activity. It was able to have anti-microbial property against different RTI causing bacteria	(Yoshida et al. 2012)
Human immunodeficiency virus (HIV)	Lamivudine (3TC), a deoxycytidine analogue, is used to treat HIV and its combination with 3-deazauridine or acivicin (both are CTPsyn inhibitors) increases anti-HIV activity significantly and halts HIV replication	(Dereuddre-Bosquet et al. 2004)