Table 1.

HIV-1 gp120 directed entry inhibitors: Classification, structural determination, antiviral and therapeutic efficacy.

Target	Inhibitor type	Molecules	Binding-site determination	Antiviral activity		Clinical trials
				In vitro efficacy	In vivo efficacy
CD4-binding site	Antibodies	VRC01-like antibodies (VRC01, 12A21, 3BNC117, etc.), HJ16, b12	Crystal structures, EM structures, mutagenesis and resistance mutation [35,43,130,131]	VRC01-like antibodies neutralize > 90% of circulating HIV-1 isolates [43,44]	VRC01 protects macaques against SHIV mucosal challenge [132]. A cocktail of bnAbs including 3BNC117 reduces plasma viral loads to undetectable levels in monkeys infected with a pathogenic SHIV [133].
	Peptides and miniproteins	M48U1, M48, M47, M48U7, M48U12, etc.	Crystal structures, mutagenesis, resistance mutation [17,50,52,53,134]	M48U1 neutralizes 90.4 % of a 180-isolate representative panel of circulating HIV-1 isolates with geometric IC50 mean of 0.13 μg/ml [50], and inhibits HIV-1(Ba-L) in human mucosal explants of cervical and colorectal tissues[18].	Used as microbicide, M48U1 blocked vaginal transmission of SHIV(162P3) in 5 out of 6 cynomolgus macaques [17] .
	Small molecules	NBD-class, DMJ-class	Crystal structures , mutagenesis, [56,135-137]	DMJ-II-121 neutralizes 83% of a 42-isolate panel of Clade B and Clade C viruses with geometric IC50 mean of 2.3 ± 0.05 μM. [56]	N.D.
		BMS-class (BMS-806, BMS-626529)	mutagenesis, resistance mutations [8,48,138]	BMS-626529 neutralizes R5-tropic viruses with EC50 of 0.4-1.7 nM, X4-tropic viruses with EC50 between 0.7 and 16.2 nM, and dual tropic virus 89.6 with EC50 57.6 nM. [8]	Oral administration of BMS-663068 for 8 days resulted in substantial declines in plasma HIV-1 RNA levels. [8]	PhaseIIb trial to investigate safety, efficacy and dose-response in ART experienced HIV-1 subjects [8]
Co-receptor binding site	Antibody fragments and nanobodies	m36, 17b scFv	Crystal structures, mutagenesis [28,31,33,67,139-144]	Yes [28]	N.D.
	Peptides Small molecules	CCR5 Nt and ECL-derived peptides	NMR data, mutagenesis [61,62,65]	Yes [59,61,62,65]	N.D.
		Tyrosine sulfate mimetic molecules	Competition assay, CD4-induction, mutagenesis [69]	Yes [69]	N.D.
Variable loops and glycan shield	Antibodies	PG9, PG16, 2G12, PGT122, 10-1074, CAP 256, VRC26.01	Crystal structures, mutagenesis, resistance mutation [79,80,145]	10-1074 and PGT121 inhibit cell-free and cell-to-cell transmission[146]	PG9 protects macaques against SHIV mucosal challenge [132].
				Yes	Used as a microbicide blocks SHIV transmission in rectal challenge [20]
	CBAs: Lectins	CVN, GRFT Benzoboroxazoles	Crystal structures, mutagenesis, resistance mutation [19,92,102,107,113,115]	Yes		Preclinical toxicity [20]
	CBAs: Synthetic			Yes		Preclinical toxicity