Targeting Kaposi's sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases

Misbahuddin M Rafeeq; Alaa Hamed Habib; Alaa F Nahhas; Najat Binothman; Majidah Aljadani; Jawaher Almulhim; Ziaullah M Sain; Mohammad Zubair Alam; Norah A Alturki; Qamre Alam; Manish Manish; Rajnish Kumar Singh

doi:10.3389/fcell.2023.1060156

Targeting Kaposi's sarcoma associated herpesvirus encoded protease (ORF17) by a lysophosphatidic acid molecule for treating KSHV associated diseases

Front Cell Dev Biol. 2023 Jan 17:11:1060156. doi: 10.3389/fcell.2023.1060156. eCollection 2023.

Authors

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, KSA.
² Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, KSA.
³ Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, KSA.
⁴ Department of Chemistry, College of Sciences and Arts, King Abdulaziz University, Rabigh, Saudi Arabia.
⁵ Department of Biological Sciences, King Faisal University, Alahsa, KSA.
⁶ Department of Microbiology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah, KSA.
⁷ Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
⁸ Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
⁹ Clinical Laboratory Science Department, College of Applied Medical Science, King Saud University, Riyadh, Saudi Arabia.
¹⁰ Medical Genomics Research Department, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.
¹¹ School of Computer and Integrative Sciences, Jawaharlal Nehru University, New Delhi, India.
¹² Molecular Biology Unit, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

Abstract

Kaposi's sarcoma associated herpesvirus (KSHV) is causative agent of Kaposi's sarcoma, Multicentric Castleman Disease and Pleural effusion lymphoma. KSHV-encoded ORF17 encodes a protease which cleaves -Ala-Ala-, -Ala-Ser- or -Ala-Thr-bonds. The protease plays an important role in assembly and maturation of new infective virions. In the present study, we investigated expression pattern of KSHV-encoded protease during physiologically allowed as well as chemically induced reactivation condition. The results showed a direct and proportionate relationship between ORF17 expression with reactivation time. We employed virtual screening on a large database of natural products to identify an inhibitor of ORF17 for its plausible targeting and restricting Kaposi's sarcoma associated herpesvirus assembly/maturation. A library of 307,814 compounds of biological origin (A total 481,799 structures) has been used as a screen library. 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) was highly effective against ORF17 in in-vitro experiments. The screened compound was tested for the cytotoxic effect and potential for inhibiting Kaposi's sarcoma associated herpesvirus production upon induced reactivation by hypoxia, TPA and butyric acid. Treatment of reactivated KSHV-positive cells with 1-oleoyl-2-hydroxy-sn-glycero-3-phospho-(1'-myo-inositol) resulted in significant reduction in the production of Kaposi's sarcoma associated herpesvirus. The study identified a lysophosphatidic acid molecule for alternate strategy to inhibit KSHV-encoded protease and target Kaposi's sarcoma associated herpesvirus associated malignancies.

Keywords: KSHV; ORF17; malignancies; protease; reactivation.

Grants and funding

This work was supported by the Department of Biotechnology, Govt. Of India, under Ramalingaswami Fellowship program (BT/RLF/Re-entry/23/2018) (to R.K.S). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.