2. Academic Validation
  3. Discovery of a Double-Stapled Short Peptide as a Long-Acting HIV-1 Inactivator with Potential for Oral Bioavailability

Discovery of a Double-Stapled Short Peptide as a Long-Acting HIV-1 Inactivator with Potential for Oral Bioavailability

  • J Med Chem. 2024 Jun 27;67(12):9991-10004. doi: 10.1021/acs.jmedchem.4c00150.
Chao Wang 1,  Wenpeng Zhang 1,  Ling Xu 2,  Jiahuang Tu 1,  Shan Su 2,  Qing Li 1,  Tao Zhang 1,  Longbo Zheng 1 3,  Huan Wang 1,  Xiaomei Zhuang 1,  Xuan Tang 4,  Yu Yuan 4,  Guangpeng Meng 4,  Lu Lu 2,  Junhai Xiao 1,  Qian Wang 2,  Shibo Jiang 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
  • 2 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, 131 Dong An Road, Shanghai 200032, China.
  • 3 Key Laboratory of Structure-based Drug Design & Discovery of the Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4 Chengdu Sintanovo Biotechnology Co., Ltd., Chengdu 610000, China.
PMID: 38888038 DOI: 10.1021/acs.jmedchem.4c00150
Abstract

Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 Infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 Infection.

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