Human endogenous retrovirus K (HERV-K, where “K” is denoting a lysine tRNA primer binding site), also known as a human teratocarcinoma-derived virus (HDTV), belongs to the family of human endogenous retroviruses (HERVs). These viruses came into being as a result of exogenous retrovirus infections developing in the course of the evolution of primates, and account for approximately 8 % of the human genome [1]. Within the HERV-K family, there are several subgroups denoted HML-1 to HML-11 (human endogenous MMTV-like), and each subgroup can be traced back to distinct germ-line infections caused by exogenous retroviruses [2].
It has been shown that the reactivation of HERVs is associated with tumors and autoimmune diseases. This is especially pronounced in the case of the HERV-K (HML-2) family, which is the most recent integration group with the smallest number of mutations and, therefore, the most biologically active to encode functional retroviral proteins and produce retrovirus-like particles [1]. The aberrant expression profiles of the HERV-K (HML-2) transcripts and their regulatory function to their proximal host genes are identified in various diseases, although up to date, there is still no explicit evidence of HERV-K (HML-2) being their direct cause.
Keeping pace with modern drug discovery trends, we have designed a new HERV-K Screening Compound Library that currently contains over 700 drug-like screening compounds selected by docking-based virtual screening against the following drug target:
The compound selection can be customized based on your requirements, cherry picking is available.
Please, contact us at orders@lifechemicals.com for any additional information and price quotations.
Endogenous retrovirus group K member 7 Pro protein (VPK7)
Recent studies have demonstrated a link between increased endogenous retrovirus group K member 7 Pro protein (VPK7) expression and decreased dehydroepiandrosterone and increased cortisol levels in the elderly [3]. Changing the ratio of these two hormones in the body of an elderly person increases the risk of inflammation of chronic diseases [4]. As some patients with reduced expression of VPK7 showed remission of chronic diseases, it is worth investigating in more detail the effect of VPK7 on the hormonal background of elderly patients with chronic diseases [5]. It is also known that this protein is present in some samples of the placenta, in tissues where tumors are formed, as well as in the brain tissue of people infected with HIV [6-9]. Therefore, further studies of these proteins can be used in various areas of clinical research [10].
Compound selection
First, we aligned two sequences using the BLAST tool to identify regions of similarity that may indicate functional and structural relationships (Fig. 1). Although various homologues display a significant level of similarity, no experimentally determined protein structure has been reported. Therefore, docking was performed in three different in silico models.
Figure 1. Pairwise sequence alignment of two sequences (full UniProtKB/P63131 and query sequence)
AlphaFold model from the UniProt database was taken as a priority. Also, the VPK7 model ranging from the 9 to 117 amino acid residues, and the all-atomic protein structures were obtained from SWISS-MODEL (QMEANDisCo Global: 0.58 ± 0.06) and I-TASSER tools. The quality of the models was evaluated in MolProbity. The Clashscore indicator included all atoms: AlphaFold = 2.07, SWISS-MODEL = 2.4, I-TASSER = 13.61. The Ramachandran analysis showed that in the AlphaFold model 94.2 % of all residues were in favored regions, 100.0 % in allowed regions, while in the SWISS-MODEL model 98.1 % of all residues were in favored regions, 100.0 % in allowed regions, and in the I-TASSER model 66.0 % of all residues were in favored regions and 89.5 % in allowed regions.
Probable active sites for each of the models were predicted. The active site, which includes the DTG catalytic motif, has been determined. For the Receptor Grid Generation, the amino acid residue D34 of the I-TASSER and SWISS-MODEL models (D26 of the AlphaFold model) was indicated as a constraint (hydrogen bond donor).
Figure 2. Structural alignment of the obtained models (green – SWISS-MODEL, blue – AlphaFold, yellow – I-TASSER, pink – DTG catalytic motif)
Docking-based virtual screening protocol (Glide by Schrödinger, SP mode) has been employed to search through the Life Chemicals HTS Compound Collection for potential VPK7 active site binders. No docking constraints have been used to allow the docking algorithm to explore as many ligands’ positions and orientations as possible.
The resulting compound libraries were compared among themselves. Only those screening compounds that interacted with all three protein models were selected. In addition, in-house MedChem and PAINS structural filters were applied.
Key features:
- Method: high-throughput virtual screening (docking)
- X-Ray data used: N/A
- Constraints: interaction site DTG
- Filters used: PAINS, toxic, reactive
- Number of compounds selected: 700
Figure 3. Binding mode of compound F6521-6618 in the hERV-K binding site (docking score = -9.149). The amino acid residues of Ser11, Thr35, and Thr113 form hydrogen bonds with amino and imino groups of the ligand.
References:
- Xue, B., Sechi, L. A., & Kelvin, D. J. (2020). Human Endogenous Retrovirus K (HML-2) in Health and Disease. Frontiers in Microbiology. https://doi.org/10.3389/fmicb.2020.01690
- Subramanian, R. P., Wildschutte, J. H., Russo, C., and Coffin, J. M. (2011). Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology 8:90. doi: 10.1186/1742-4690-8-90
- Dillon DG, Gurdasani D, Riha J, Ekoru K, et al. African Partnership for Chronic Disease Research (APCDR). Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis. Int J Epidemiol. 2013 Dec;42(6):1754-71. doi: 10.1093/ije/dyt198. Erratum in: Int J Epidemiol. 2016 Dec 1;45(6):2210-2211. PMID: 24415610; PMCID: PMC3887568.
- Bauer ME, Wieck A, Petersen LE, Baptista TS. Neuroendocrine and viral correlates of premature immunosenescence. Ann N Y Acad Sci. 2015 Sep;1351:11-21. doi: 10.1111/nyas.12786. Epub 2015 May 5. PMID: 25943573.
- Laderoute MP. A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease. Discov Med. 2015 Dec;20(112):379-91. PMID: 26760982.
- Wang-Johanning F, Frost AR, Johanning GL, Khazaeli MB, LoBuglio AF, Shaw DR, Strong TV. Expression of human endogenous retrovirus k envelope transcripts in human breast cancer. Clin Cancer Res. 2001 Jun;7(6):1553-60. PMID: 11410490.
- Armbruester V, Sauter M, Krautkraemer E, Meese E, Kleiman A, Best B, Roemer K, Mueller-Lantzsch N. A novel gene from the human endogenous retrovirus K expressed in transformed cells. Clin Cancer Res. 2002 Jun;8(6):1800-7. PMID: 12060620.
- Johnston JB, Silva C, Holden J, Warren KG, Clark AW, Power C. Monocyte activation, and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol. 2001 Oct;50(4):434-42. doi: 10.1002/ana.1131. PMID: 11601494.
- Kleiman A, Senyuta N, Tryakin A, Sauter M, Karseladze A, Tjulandin S, Gurtsevitch V, Mueller-Lantzsch N. HERV-K(HML-2) GAG/ENV antibodies as an indicator for therapy effect in patients with germ cell tumors. Int J Cancer. 2004 Jun 20;110(3):459-61. doi: 10.1002/ijc.11649. PMID: 15095315.