Table 3.

Antiviral activity of selected G4 ligands.

G4 Ligand (Chemotype)	Structure in Figure	Virus	Effects	Refs.
TMPyP4 (porhyrine)	6	HIV-1	Blocked viral replication in lymphocyte T cells with established HIV-1 latency.	[154]
			Inhibition of viral infectivity.	[155]
			Enhanced killing of latently infected cells when in combination with latency reversing agents.	[156]
		KSHV	Inhibited viral DNA replication; reduced in 60% the viral episome copy numbers; inhibited LANA1 translation in KSHV infected cells.	[157,158]
		HCV	Promoted viral RNA polymerase stalling.	[159]
		EBOV	Reduced transcription of L gene (encodes for viral RNA-dependent RNA polymerase) and impaired replication of viral genome.	[160]
		HSV-1	Showed good antiviral activity at microM concentrations; did not inhibited virus DNA replication or entry but inhibited virus release by the cells.	[161]
		ZIKV	Inhibited viral growth, genome replication and protein expression.	[162]
		SARS-CoV-2	Inhibited replication and gene expression of virus RNA G4-forming sequences in in-vitro assays	[145]
Acridine C8	7	HPV	The exposure of cervical cells to C8 at 0.25 microM induced a >100-fold decrease in HPV18 viral titre; C8 probably affects viral genome encapsidation rather than genome amplification.	[163]
BRACO-19 (acridine)	4	HIV-1	Reduced viral titre to undetectable levels in latently infected cells.	[154]
			Blocked RT progression in-vitro, which was counteract by viral Ncp7, a protein known to unfold RNA G4s.	[164,165]
			Antiviral activity at microM concentrations.	[164]
			Reduced proviral LTR promoter activity.	[165]
			Enhanced killing of latently infected cells when in combination with latency reversing agents.	[156]
		HSV-1	Antiviral activity (IC50~8 µM) with inhibition of viral DNA synthesis.	[166]
		HHV-6	Reduction of viral genome integration in human chromosomes at telomeres.	[167]
		EBV	Reduced viral genome copy numbers in infected lymphocytes; reduced transcription of viral proteins EBNA2 and EBNA3A; reduced EBNA1-dependent DNA replication.	[168]
		HBV	Enhanced preS2/S gene promoter activity, which product regulates production of the HBV surface antigen and virion secretion.	[169]
		ZIKV	Inhibited viral growth, genome replication and protein expression.	[162]
		SARS-CoV-2	Inhibited replication and gene expression of virus RNA G4-forming sequences in in-vitro assays	[145]
c-exNDI (naphetalene Diimide)	6	HIV-1	Strong antiviral activity (IC50 < 25 nM).	[170]
		HSV-1	Antiviral activity (IC50~18 nM) with inhibition of viral DNA synthesis.	[171]
Pyridostatin	6	EBV	Reduced EBNA1 synthesis and recognition of EBV-infected cells by virus-specific T cells.	[137]
		HBV	Enhanced preS2/S gene promoter activity.	[169]
		ZIKV	Inhibited mRNA synthesis, virus cytopathic effect and viral NS2B-NS3 protease activity in infected Vero cells, particularly during postinfection treatment.	[172]
PDP (pyridostatin)	7	HCV	Promoted viral RNA polymerase stalling. In-vivo G4-mediated antiviral activity in the low microM range.	[159]
		SARS- CoV-2	Inhibited translation of nucleocapsid protein N, in-vitro and in-vivo.	[147]
CX-5461 (quinolone)	4	CMV	Reduced viral titre by 2 log, acting at the viral DNA replication stage.	[173]
PhenDC3 (phenanthroline)	6	EBV	Inhibited nucleolin binding to EBNA1 mRNA G4s and increased the endogenous EBNA1 levels in EBV-infected cells.	[139]
		KSHV	Inhibited viral DNA replication by stalling the replication fork at the TR level; consequent reduction of viral episome copy numbers.	[157]
		HCV	Inhibited viral replication in cells.	[174]
		SARS-CoV-2	Inhibited in-vitro the SUD-NM/TRF2 G4 interaction with an IC50 = 51 nM.	[146]
BzSeX (Benzoseleno xanthene)	7	IAV	Reduced viral titers in-vitro, with downregulation of TMPRSS2 expression, a transmembrane serine protease essential for virus entry into the host cells	[156]
ribavirin	7	SARS-CoV-2	Antiviral activity; reduced expression of TMPRSS2 and AC2; inhibited TMPRSS2 enzymatic activity.	[152]

dsDNA viruses: HSV-1 Herpes Simplex Virus 1; HHV-6 Human Herpesviruses 6A/6B; KSHV Kaposi’s Sarcoma-associated Herpes virus; HPV Human Papilloma Virus; EBV Epstein–Barr Virus; CMV Human cytomegalovirus; HBV Hepatitis B Virus. (+)ssRNA viruses: HIV-1 Human Immunodeficiency Virus 1; HCV Hepatitis C Virus; EBOV Ebola Virus; SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus-2; ZIKV Zika Virus; IAV Influenza A virus. Legend: EBNA: EBV-Encoded Nuclear Antigen; LANA1: Latency Associated Nuclear Antigen 1, a regulatory protein of virus latency; LTR: Long terminal Repeats; RT: Reverse Transcriptase; TR: Terminal Repeats (a guanine rich region).