HIV-1, entre la proteina CCR5 y Des1 ??

Primero:

Binding modes of CCR5-targetting HIV entry inhibitors: Partial and full antagonists.

Wang T, Duan Y.

Genome Center and Bioinformatics Program and Department of Applied Science, 431 East Health Science Drive, University of California, Davis, CA 95616-8816, USA.

Since the CC-chemokine receptor 5 (CCR5) was identified as a major co-receptor for human immunodeficiency virus type 1 (HIV-1) entry into a host cell, CCR5-targetting HIV entry inhibitors have been developed and some of them are currently in clinical trials. Most of these inhibitors also inhibit the physiological chemokine reaction function of CCR5, which is so far considered to be safe to patients based on the observation that individuals that naturally lack CCR5 do not show apparent health problems. Nevertheless, to minimize the toxicity and side effects, it would be ideal to preserve the chemokine receptor activity. In this work, we simulated the flexible docking of two small molecule inhibitors to CCR5 in a solvated phospholipid bilayer environment. One of the inhibitors, aplaviroc has a unique feature of preserving two of the natural chemokine ligands binding to CCR5 and subsequent activation whereas the other one, SCH-C fully blocks chemokine-CCR5 interactions. Our results revealed significantly different binding modes of these two inhibitors although both established extensive interaction networks with CCR5. Comparison of the different binding modes suggests that avoiding the deep insertion of inhibitors into the transmembrane helix bundle may be able to preserve chemokine-CCR5 interactions. These results could help design HIV co-receptor activity-specific inhibitors.

PMID: 18249144 [PubMed - as supplied by publisher]

Structural and molecular interactions of CCR5 inhibitors with CCR5.

Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, Norman R, Takaoka Y, Ding J, Arnold GF, Arnold E, Mitsuya H.

Department of Hematology, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan.

We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1.

PMID: 16476734 [PubMed - indexed for MEDLINE]

AND:

Summary

The lateral organization of lipids in cell membranes is thought to regulate numerous cell processes. Most studies focus on the coexistence of two fluid phases, the liquid crystalline (l_d) and the liquid-ordered (l_o); the putative presence of gel domains (s_o) is not usually taken into account. We show that in phospholipid:sphingolipid:cholesterol mixtures, in which sphingomyelin (SM) promoted fluid l_o domains, dihydrosphingomyelin (DHSM) tended to form rigid domains. Genetic and pharmacological blockade of the dihydroceramide desaturase (Des1), which replaced SM with DHSM in cultured cells, inhibited cell infection by replication-competent and -deficient HIV-1. Increased DHSM levels gave rise to more rigid membranes, resistant to the insertion of the gp41 fusion peptide, thus inhibiting viral-cell membrane fusion. These results clarify the function of dihydrosphingolipids in biological membranes and identify Des1 as a potential target in HIV-1 infection.