Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors

Abstract

CD4 mimics are small molecules that inhibit the protein-protein interaction between gp120 and CD4, which is a key interaction for the entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono-cyclohexyl-type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR-329, a novel 1-azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti-HIV activity than a previously described lead HAR-171, and modeling results indicated the formation of advantageous interactions by the para-chlorophenyl moiety of YIR-329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono-cyclohexyl-type CD4 mimics with a guanidino group, such as YIR-819 (N(1) -(4-chlorophenyl)-N(2) -(1-(2-(N-(amidino)glycinamide)ethyl)-2-cyclohexylpiperidin-4-yl)oxalamide) and YIR-821 (1-(2-(5-guanidinovaleramide)ethyl derivative of YIR-819), were identified that exhibit approximately fivefold more potent anti-HIV activity than YIR-329. In combination with a neutralizing antibody, their anti-HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR-819 and YIR-821 represent useful lead compounds for the further development of HIV-1 entry inhibitors and could potentially be useful for co-administration with neutralizing antibodies for the treatment of HIV infection and AIDS.

Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

“…The on rates of CD4mc binding are critical determinants of the binding affinity of these compounds for the functional Env trimer. As might be expected for any ligandprotein interaction, the enthalpic contributions of an increased number of bonds between the CD4mc and gp120 result in higher affinity and increased potency (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). However, because CD4mc induce conformational changes in Env in the process of binding, the CD4mc-Env binding affinity is strongly influenced by the propensity of the Env trimer to undergo conformational changes (i.e., Env reactivity) (51,52).…”

“…They include soluble CD4 (sCD4), enhanced CD4 (eCD4), sCD4 miniproteins, and small-molecule CD4-mimetic compounds (CD4mc) (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). All of these inhibitors bind gp120 near the natural binding site for CD4, a well-conserved surface element adjacent to a pocket located at the interface of the gp120 inner domain, outer domain, and bridging sheet (32)(33)(34)(35)(36)(37)(38)(39).…”

“…The hits from this screen, NBD-556 and the closely related NBD-557, exhibited only weak antiviral activity against a very limited number of natural HIV-1 variants (30)(31)(32). Iterative, structure-based modifications of these prototypic CD4mc have led to significant improvements in the potency and breadth of their anti-HIV-1 activity (32)(33)(34)(35)(36)(37)(38)(39)(40)(41). Of particular importance was the replacement of the chemically intractable tetramethylpiperidine ring of NBD-556 and NBD-557 with an indane ring that allowed multiple substitutions (37,38).…”

HIV‐1 Entry Inhibitors: A Review of Experimental and Computational Studies

“…The guanidino moiety in the structure of this series of compounds, in which the piperidine nitrogen atom is directly amidinated or have a linker which is shorter than the linker in the structure of 19 , cannot interact efficiently with Asp368. Compound 18 with the longest linker had the best anti‐HIV‐1 activity (IC 50 = 2.6 μ m ) …”

Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution

“…We and others have been exploring the potential of NBD-556-derived CD4mc as a novel class of HIV entry inhibitor (Madani et al, 2004, 2008, 2014, 2016, 2017; Narumi et al, 2010, 2011, 2013; Yamada et al, 2010; Yoshimura et al, 2010; Lalonde et al, 2011, 2012, 2013; Courter et al, 2014; Richard et al, 2015; Melillo et al, 2016; Mizuguchi et al, 2016; Ohashi et al, 2016). The binding of CD4mc in the Phe 43 cavity blocks CD4-gp120 interaction and, induces conformational changes in gp120 similar to those observed upon sCD4 binding ( Figure 2B ) (Schon et al, 2006; Haim et al, 2009; Curreli et al, 2014; Kwon et al, 2014).…”