Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-ray structure and resistance study.

We previously identified two small-molecule CD4 mimetics--NBD-556 and NBD-557--and synthesized a series of NBD compounds that resulted in improved neutralization activity in a single-cycle HIV-1 infectivity assay. For the current investigation, we selected several of the most active compounds and assessed their antiviral activity on a panel of 53 reference HIV-1 Env pseudoviruses representing diverse clades of clinical isolates. The selected compounds inhibited tested clades with low-micromolar potencies.

Dual-acting stapled peptides target both HIV-1 entry and assembly.

Background: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (K(d) ~ 1 μM) compared to CAI (K(d) ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.

Progress in identifying peptides and small-molecule inhibitors targeted to gp41 of HIV-1.

During the last decade, a great number of activities have been geared in identifying newer targets for inhibiting HIV infection as well as understanding the targets for already identified anti-HIV-1 agents. The success in converting a proof-of-concept peptide T-20 (previously named DP-178), from the C-terminal heptad repeat (CHR) region of the envelope glycoprotein gp41 of HIV-1, to a drug named enfuvirtide was one of the phenomenal successes in HIV-1 drug discovery research that has been made in recent years. There were many reports of modifying peptides from the N-terminal heptad repeat and CHR regions with the objective of improving their activity.

Application of 3D-QSAR techniques in anti-HIV-1 drug design--an overview.

Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV-1.

Generation of predictive pharmacophore models for CCR5 antagonists: study with piperidine- and piperazine-based compounds as a new class of HIV-1 entry inhibitors.

Predictive pharmacophore models were developed for a large series of piperidine- and piperazine-based CCR5 antagonists as anti-HIV-1 agents reported by Schering-Plough Research Institute in recent years. The pharmacophore models were generated using a training set consisting of 25 carefully selected antagonists based on well documented criteria. The activity spread, expressed in K(i), of training set molecules was from 0.