Cordycepin analogs of 2',5'-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase

Abstract

Analogues of 2',5'-oligoadenylates (2-5A), the cordycepin (3'-deoxyadenosine) core trimer (Co3) and its 5'-monophosphate derivative (pCo3), were shown to display pronounced anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. Treatment of HIV-1 infected H9 cells with 1 microM Co3 or pCo3 resulted in an almost 100% inhibition of virus production. The compounds were encapsulated in liposomes targeted by antibodies specific for the T-cell receptor molecule CD3. Substitution of one or two cordycepin units in Co3 or pCo3 decreased the antiviral activity of the compounds. pCo3 did not stimulate 2-5A-dependent ribonuclease L activity and displayed no effect on the amount of cellular RNA and protein. At a concentration of 10 microM the cellular DNA polymerases alpha, beta, and gamma were almost insensitive toward Co3 or pCo3. In contrast, these compounds reduced the activity of HIV-1 reverse transcriptase (RT) by 90% at a concentration of 10 microM if the viral RNA genome and the cellular tRNALys.3 was used as template/primer system; if the synthetic poly(A).(dT)10 was used as template/primer, no marked inhibition was observed. Dot-blot, gel-retardation, and cross-linking assays showed that Co3 or pCo3 interfere with the binding site of tRNALys.3 to RT. These results indicate that inhibition of RT at the level of initiation of the enzymic reaction is a novel approach to inhibit HIV-1 replication.

Cordycepin induces apoptosis by enhancing JNK and p38 kinase activity and increasing the protein expression of Bcl-2 pro-apoptotic molecules

“…Cordycepin (3-deoxyadenosine, 3'-dA) is the main active ingredient. Early studies have shown that cordycepin has various biological activities, which include inhibiting inflammation (Kim et al, 2006), inhibiting platelet aggregation (Cho et al, 2007), strengthening the immune system (Zhou et al, 2008), inhibiting the polyadenylation of mRNA (Lallas et al, 2004), and inhibiting human immunodeficiency virus infection (Müller et al, 1991). Studies also have shown that cordycepin has significant anti-tumor effects such as inhibiting cell proliferation and metastasis (Nakamura et al, 2005;Chang et al, 2008;Shi et al, 2008), inducing apoptosis (Wehbe-Janek et al, 2007;Wu et al, 2007;Thomadaki et al, 2008), and interfering with cell signaling pathways (Lee et al, 2009;Wong et al, 2010).…”

Comparison of growth‐inhibiting activities of Cordyceps militaris and Paecilomyces japonica cultured on Bombyx mori pupae towards human gastrointestinal bacteria

“…8 Submerged cultivated C. militaris is found to secrete cordycepin into the environment. 20 Cordycepin is found to possess antitumor activity, 21 inhibition of nuclear RNA synthesis in nerve and glial cells, 22 and antiviral activity towards HIV-1 in vitro, 23 as well as antiprotozoal effect 24 and insecticidal activity against Plutella xylostella (L.). 25 Structure-growth inhibition relationships in intestinal organisms have been studied.…”

Cordycepin increases sensitivity of Hep3B human hepatocellular carcinoma cells to TRAIL-mediated apoptosis by inactivating the JNK signaling pathway

“…This activity has been well described in vitro with purified RNA polymerases and poly(A) polymerases from a number of organisms, including yeasts and mammals (9,10). Cordycepin has anticancer activities including induction of apoptosis, DNA double-strand break activity, and cell cycle arrest in cancer cells (11)(12)(13)(14)(15).…”